
==== Front
Stem Cell Res Ther
Stem Cell Res Ther
Stem Cell Research & Therapy
1757-6512
BioMed Central London

39227906
3912
10.1186/s13287-024-03912-z
Review
Research progress and application prospect of adipose-derived stem cell secretome in diabetes foot ulcers healing
Wan Xiaofen 12
Ni Xuejun 12
Xie Yunjia 1
Chen Lu 1
Cai Beichen 12
Lin Qian 1
Ke Ruonan 1
Huang Tao 1
Shan Xiuying xiuyingshan@fjmu.edu.cn

12
http://orcid.org/0000-0001-6253-2713
Wang Biao biaowang@fjmu.edu.cn

12
1 https://ror.org/030e09f60 grid.412683.a 0000 0004 1758 0400 Department of Plastic Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005 China
2 grid.256112.3 0000 0004 1797 9307 Department of Plastic Surgery, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212 China
4 9 2024
4 9 2024
2024
15 27917 7 2024
29 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
Diabetic foot ulcers (DFUs) are chronic wounds and one of the most common complications of diabetes, imposing significant physical and mental burdens on patients due to their poor prognosis and treatment efficacy. Adipose-derived stem cells (ADSCs) have been proven to promote wound healing, with studies increasingly attributing these beneficial effects to their paracrine actions. Consequently, research on ADSC secretome as a novel and promising alternative for DFU treatment has been extensively conducted. This article provides a comprehensive review of the mechanisms underlying refractory DFU wounds, the secretome of ADSCs, and its role in promoting wound healing in diabetes foot ulcers. And the review aims to provide reliable evidence for the clinical application of ADSC secretome in the treatment of refractory DFU wounds.

Keywords

Diabetic foot ulcers
Adipose-derived stem cells
Secretome
Wound healing
Young and Middle-aged Key Personnel Training Project of Fujian Provincial Health Commission2020GGB029 Shan Xiuying Joint Funds for the Innovation of Science and Technology, Fujian Province2020Y9124 Shan Xiuying Natural Science Fundation of Fujian Province2021J01244 Ni Xuejun issue-copyright-statement© BioMed Central Ltd., part of Springer Nature 2024
==== Body
pmcBackground

Diabetes mellitus (DM) is a severe metabolic condition affecting over 10.5% of the world’s adult population [1], with China currently having the highest number of diabetic patients globally [2]. DFUs, characterized by chronic and difficult-to-heal wounds, are one of the most common complications of DM, with high morbidity, recurrence, amputation, and mortality rates, as well as high treatment costs, imposing a substantial weight on patients, families and society [3]. The current clinical treatment for diabetic foot ulcer wounds focuses on debridement, anti-infection, improvement of blood supply to the lower limbs and foot decompression and braking [4], but these methods often have poor therapeutic efficacy. In recent years, new strategies, such as various wound debridement techniques, dressings, gas therapy, wound physical therapy, skin substitutes, cell products, medications, negative pressure wound therapy, have shown promise for the treatment of severe diabetic foot ulcers [5]. However, in 2023 the International Working Group on the Diabetic Foot (IWGDF) incorporated the feasibility and equity of intervention implementation into the assessment criteria and made 29 separate recommendations. They concluded that existing strategies do not provide a cost-effective solution to this persistent condition, highlighting the need for continuous exploration of new treatments [6].

Since the first clinical application of mesenchymal stem cells (MSCs) therapy in 1995, the therapeutic capacity of stem cell therapy for various diseases has gained significant attention [7]. Among these, ADSCs have consistently demonstrated the ability to enhance the process of wound healing [8–10], a finding supported by preliminary studies from our research team [11]. Moreover, the secretome of ADSCs has demonstrated significant therapeutic effects in wound healing [12], although the underlying mechanism remains unclear. To further investigate, we conducted a literature search on PubMed and Web of Science using keywords such as ‘adipose-derived stem cells,’ ‘secretome,’ and ‘diabetic foot ulcers’ to identify relevant cell studies, animal research, and clinical trials published in the past 10 years. This paper reviews the mechanisms of delayed healing in DFUs and the role of the ADSC secretome in promoting wound healing in diabetic foot ulcers, aiming to establish a reliable basis for the clinical application of ADSC secretome in treating difficult-to-heal DFUs.

Mechanisms of delayed healing in diabetic foot ulcer wounds

The process of skin wound healing typically involves four consecutive and overlapping stages: hemostasis, inflammation, proliferation, and remodelling [13]. However, this process is hindered by various factors in diabetic foot ulcer wounds, leading to delayed healing (Fig. 1).Fig. 1 Mechanisms of diabetes foot ulcers (Created with BioRender.com). PKC Protein kinase C, AGE Advanced glycation end product, TNFα Tumor Necrosis Factor-alpha, IL Interleukin, ROS Reactive oxygen specie, EPC Endothelial progenitor cell, EC Endothelial cell, ECM Extracellular matrix

Neuropathy

Diabetic neuropathy occurs in nearly 90% of diabetic foot ulcers [14]. It is a peripheral neurodegenerative disease primarily affecting sensory and autonomic nerves, and eventually, motor nerves [15]. Sensory neuropathy leads to neuropathic pain and/or sensory loss, while motor neuropathy causes muscle atrophy and functional deterioration, both of which result in uneven foot loading, increased plantar pressure, subcutaneous edema, and an 8 to 18-fold increased risk of falls and foot ulcers, and a 2 to 15-fold increased risk of lower limb amputation. Autonomic neuropathy impairs the function of sweat and sebaceous glands in the feet, coupled with vasomotor paralysis, leading to dry, cracked, and damaged skin. This impairs the skin’s natural barrier function, providing an entry point for bacteria and other microorganisms [16]. The above biological, behavioral, or combined effects have resulted in the elevated recurrence rate of DFUs [17].

Further exploration of its mechanism revealed that hyperglycemia, dyslipidemia, and/or insulin resistance promote the activation of the polyol and hexosamine pathways, the accumulation of protein kinase C (PKC) subtypes and advanced glycation end products (AGEs), as well as the loss of insulin signaling, collectively leading to imbalanced mitochondrial redox status and excessive formation of reactive oxygen species (ROS) [18]. Subsequently, Schwann cells and dorsal root ganglion (DRG) neurons undergo metabolic and oxidative damage, inducing axonal degeneration, loss of neurotrophic signaling, and local blood supply decreases, which ultimately causes irreversible damage to the nervous system [15]. Preventing neurodegeneration can improve healing, such as using the C-X-C chemokine receptor type 4 (CXCR4) antagonist AMD3100 to improve wound healing in db/db mice by selectively targeting the CXCR4 receptor, which is lacking in DRG neurons [14].

Angiopathy

Peripheral vascular dysfunction is one of the main causes of DFUs formation in most diabetic patients. Diabetic vasculopathy can be divided into macroangiopathy and microangiopathy. The former manifests primarily as atherosclerosis, with the formation of plaques that rupture to trigger peripheral arterial thrombosis, particularly in the diabetic setting, leading directly to arterial occlusion and lower limb ischemia, ultimately resulting in DFUs [19]. Research confirms hyperglycemia in diabetes can lead to glycated hemoglobin, vascular narrowing, red blood cell membrane changes, dyslipidemias, and foam cell formation from macrophages, triggering the formation of atherosclerosis, that causes vascular damage, and stimulating endothelial cells to generate ROS. And ROS utilizes the Nuclear Factor-kappa B (NF-κB) pathway to induce leukocyte recruitment and apoptosis, leading to inflammation, ischemia, and neuronal cell damage [20]. The latter manifests as abnormalities in microvascular structure and function, and important theories that can explain this phenomenon are the hemodynamic hypothesis and capillary steal syndrome [21]. Furthermore, additional research has confirmed that diabetic neuropathy can be caused by microvascular ischemia involving the nerve [22]. Therefore, vascular repair and reconstruction are crucial for wound healing.

However, vascular regeneration exists in two modes, one being angiogenesis, which denotes the growth of new blood vessels either by budding or non-budding forms, based on existing capillaries or venules through proliferation, differentiation, and migration of endothelial cells. The other mode is vasculogenesis, which involves endothelial progenitor cells (EPCs) from bone marrow that differentiate into endothelial cells to form new blood vessels [23]. Nevertheless, fully developed endothelial cells are specialized cells that have reached their final stage of differentiation and have a restricted ability to proliferate, especially when functioning in a diabetic environment, thus inhibiting angiogenesis [24]. Therefore, EPCs significantly contribute to angiogenesis by mobilizing, proliferating, nesting and differentiating into endothelial cells to promote angiogenesis and accelerate wound healing [25]. Nonetheless, diabetic patients experience reduced counts and functionality of circulating EPCs, leading to impaired neovascularization and delayed wound healing [26].

Infection and immune dysfunction

50% of diabetic foot ulcers will develop infections, and recurrent or chronic ulcers increase the risk of infection [27]. Inadequate blood flow to the lower extremities, along with various neuropathies, elevates the likelihood of Diabetic Foot Infections (DFIs) [19]. Diabetic infections result from the combined effects of pathogenic virulence and immune dysfunction.

A multi-omic study found that in the majority of mild to moderate DFIs, Staphylococcus aureus and Streptococcus species are abundant and highly active, with a significant enrichment of related virulence genes. In extreme DFIs, individuals demonstrate increased microbial diversity, encompassing Pseudomonas aeruginosa and other bacteria, along with Candida albicans and other fungi. The variance in gene expression of these organisms suggests an abundance of multi-species virulence genes [28]. When planktonic pathogenic bacteria or fungi, together with certain bacteria previously considered non-pathogenic or unable to sustain chronic infections, form a polymicrobial pathogenic biofilm, it can protect them from the immunological response of the host and the impact of antibiotics, leading to multidrug resistance and delayed wound healing [29].

Furthermore, persistent DFIs are closely associated with abnormal immune cell activity. In the diabetic microenvironment, neutrophil extracellular traps (NETosis) are dysregulated, resulting in an overproduction of pro-inflammatory cascades, cytokines, and ROS, thereby delaying wound healing [30]. Concurrently, sustained hyperglycemia levels upregulate pro-inflammatory factors such as Tumor Necrosis Factor-alpha (TNFα), Interleukin-1 beta (IL-1ß), and Interleukin-6 (IL-6), increasing macrophage sensitivity to these cytokines while downregulating the expression of Cluster of Differentiation 36 (CD36) and Class B Scavenger type I receptors required for phagocytic activity, hindering M1 macrophage phagocytic activity, and promoting a senescent-associated secretory profile (SASP) in macrophages, which ultimately leads to impaired polarization from pro-inflammatory (M1) to anti-inflammatory (M2) phenotype [31]. Additionally, macrophages can secrete large amounts of proteases, including matrix metalloproteinase-9 (MMP-9), which degrades newly synthesized extracellular matrix (ECM) and hinders cell migration, thus inhibiting wound healing [32, 33].

Adipose-derived stem cells secretome

Adipose-derived stem cells

In 2001, Zuk et al. discovered and isolated ADSCs from human adipose tissue using a negative pressure suction technique [34]. ADSCs provide benefits such as minimal invasiveness, easy accessibility, low immunogenicity, high regenerative potential, low carcinogenicity, and no ethical concerns, making them a prominent focus of research. Their therapeutic potential in treating a range of diseases, including wound healing, is well-established [35]. ADSCs fall into the mesenchymal stem cell category and display typical mesenchymal stem cell characteristics in vitro: (1) ADSCs adhere to plastic culture bottles under standard culture conditions; (2) they exhibit similar surface markers to bone marrow mesenchymal stem cells (BMSCs), such as CD13, CD29, CD49d, CD73, CD90, CD105, and Stro-1, but do not express CD45, CD14, CD133, and CD144 [36]; (3) they possess multipotent differentiation potential, capable of differentiating into adipocytes, osteocytes, chondrocytes, hepatocytes, endothelial cells, keratinocytes, Schwann cells, myocytes, and pancreatic acinar cells, and can be rewired into induced pluripotent stem cells (iPSCs) [37, 38]. Despite these advantages, challenges remain in standardized cell extraction, stable storage, and transportation. High costs further complicate the widespread use of traditional ADSC cell therapy [39].

Adipose-derived stem cells secretome

While recent studies have shown that ADSCs mediate wound repair and regeneration through paracrine signaling by secreting various bioactive factors, known as ADSC secretome [40]. In 2000, the concept of the secretome was first introduced by Tjalsma to describe all proteins released by bacteria out of cells and their secretion mechanisms [41]. Currently, the secretome is broadly defined as various soluble factors released directly from cells into the extracellular space, and the carriers including extracellular vesicles (EVs) and migrasomes that transport these factors [42]. Numerous studies use conditioned media to obtain the secretome, exploring its role in various diseases and tissue repair [43]. Gregorio et al. identified a total of 569 factors through proteomic analysis of ADSC-conditioned medium (ADSC-CM) [44]. Presently, EVs are the most extensively studied components of the secretome [45]. According to the latest international guidelines, “Minimal Information for Studies of Extracellular Vesicles 2023 (MISEV2023),” EVs are defined as particles released by cells, enclosed by a lipid bilayer, and incapable of self-replication due to the lack of a functional nucleus [46]. Evs are broadly classified into three subtypes based on their biogenesis, release pathways, size, content, and functions: apoptotic vesicles (apoVs), 50–5000 nm; microvesicles (MVs), 100–1000 nm; and exosomes (Exos), 30–200 nm [47]. In terms of molecular composition, EVs include abundant proteins, lipids, nucleic acids, polysaccharides, playing roles in intercellular communication and participating in physiological processes like cell proliferation, apoptosis, migration, and differentiation. They show great potential in wound repair and tissue regeneration [48]. Furthermore, in 2014, Ma et al. first observed ellipsoid membrane-bound structures secreted by migrating cells in vitro, defining them as migrasomes [49]. Migrasomes are rich in signaling molecules such as chemokines, cytokines, and angiogenic factors, fulfilling a crucial function in the spatially precise delivery of these signaling molecules, influencing key physiological processes including organ morphogenesis and angiogenesis [50]. Therefore, using ADSC secretome to enhance tissue regeneration may be a promising alternative to traditional ADSCs therapy. Table 1 summarizes the key components of the ADSC secretome.Table 1 The key components of the ADSC secretome

	Category	Component	References	
Soluble Protein	Growth factors	VEGF, PDGF, KGF, EGF, TGF-β, HGF, bFGF, IGF, BDNF, GDNF, NGF, IGFBP1, IGFBP2, CNTF, NT-3 and NT-4	[52, 59, 87–89]	
Cytokines	IL-1α, IL-1β, IL-2, IL-4, I-5, TL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-15, MCP-1, GM-CSF, IFN-γ, RANTES	[90]	
Chemokines	CXCL1, CXCL2, CXCL3, CXCL5, CXCL12, CCL27, CCL2, CCL5, CCL27, CX3CL1, XCL1	[91–94]	
Carriers	EVs	apoVs, MVs, Exos	[47]	
Migrasomes		[64]	

Mechanism of ADSC secretome in promoting diabetic foot ulcer wound healing

Research has demonstrated that the secretome of ADSCs promotes wound healing through multiple mechanisms. These include improving neuropathy, promoting angiogenesis, modulating inflammation and immune response, as well as facilitating tissue remodeling and re-epithelialization (Fig. 2). The following sections will elucidate these processes in detail.Fig. 2 Mechanism of ADSC secretome in promoting diabetic foot ulcers (Created with BioRender.com). ADSC Adipose-derived stem cell, EVs Extracellular Vesicles, apoVs Apoptotic Vesicles, MVs Microvesicles, Exos Exosomes, EPC Endothelial progenitor cell, EC Endothelial cell, ECM Extracellular Matrix, T cell T lymphocyte cell, B cell B lymphocyte cell, NK cell Natural Killer cell

Improvement of neuropathy

Neuropathic changes significantly contribute to the occurrence and development of diabetic foot. Research has demonstrated that the neuroprotective effects of the ADSC secretome are attributed to the inhibition of apoptosis, reduction of neuronal energy depletion, promotion of cerebral blood vessel formation, and reduction in astrocyte proliferation [51]. ADSCs secrete numerous neurotrophic factors that promote nerve regeneration, including brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), nerve growth factor (NGF), and neurotrophins-3 and -4 (NT-3 and NT-4) [52]. Chen et al. found that ADSC-EVs carrying miR-130a-3p promote Schwann cell proliferation and prevent diabetic peripheral neuropathy through the DNMT1/NRF2/HIF1α/ACTA1 axis [53]. Yin et al. found that ADSC-Exos enhance the autophagy of injured Schwann cells induced by nerve damage by reducing miRNA-26b targeting Kpna2, thereby promoting remyelination [54]. Additionally, studies have shown that the bioactive medium mixture present in ADSC-CM can transform a neurodestructive/pro-inflammatory microenvironment into a neuroprotective/anti-inflammatory one, improve thermal mechanical sensitivity, restore epidermal nerve fiber density, stimulate Schwann cell proliferation, inhibit neuronal autophagy and apoptosis, and promote remyelination to enhance nerve regeneration [44].

Promoting angiogenesis

Vascular regeneration is crucial for wound healing as it increases immune cell recruitment, provides oxygen and nutrients to metabolically active wounds, and removes toxic metabolites and waste. Numerous studies have shown that ADSCs upregulate the expression of miR-125a [55], miR-126 [56], miR-128 [57], miR-132 [58], increase the secretion of vascular growth factors such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF), regulate endothelial cell proliferation and migration, promote vascular regeneration, and improve wound healing efficiency [59]. In addition, the miR-21-5p-enriched secretion of ADSCs activates the PI3K/AKT/PTEN or mTOR signaling pathway, promoting the expression of HIF-1α and VEGF which contributes to vascular regeneration in the diabetic microenvironment [60]. Research has also shown that ADSC-Exos upregulate the expression of lncRNA-SENCR through EGR-1 to activate the DKC1/VEGF-A axis, promoting the proliferation and migration of human umbilical vein endothelial cells (HUVECs), thus improving vascular regeneration, and facilitating wound healing [61]. Similarly, Zhang et al. found that ADSC-exos can regulate the expression of SIRT3 and its downstream protein SOD2, improve oxidative stress and inflammatory microenvironment, improve endothelial cell dysfunction caused by hyperglycemia, promote vascular regeneration, and further facilitate the healing of chronic diabetic wounds [62]. Li et al. found that overexpression of Nrf2 in ADSC-Exos can increase granulation tissue formation, vascular regeneration, and growth factor expression levels, decrease levels of inflammation and oxidative stress-related proteins, and eventually promote wound healing in rat diabetic foot ulcers [63]. In addition, SDF-1 was detected in MSC migratory bodies by Deniz et al. [64], and Zhang et al. found that SDF-1 mediates the mobilization of endothelial progenitor cells and neovascularization, promoting wound healing in diabetic mice [65].

Modulation of inflammatory and immune responses

Diabetic foot ulcer non-healing is related to excessive oxidative stress, persistent inflammatory response, and imbalanced activation of signaling pathways, which lead to abnormal immune cell function, induce excessive inflammation, and ultimately disrupt the microenvironment for wound healing. ADSCs secrete pro-inflammatory cytokines (IL-7, IL-8, IL-9, IL-11, IL-12, IL-15, IL-17 and INF-γ) and anti-inflammatory cytokines (IL-1Ra, IL-4, IL-10, and IL-13) [35]. The release of these factors is enhanced under inflammatory conditions, resulting in inhibition of T cell function (proliferation, differentiation, and cytotoxicity), B cell function, NK cell cytotoxicity, decreased maturation and activation of dendritic cells, and increased regulatory T cells, effectively participating in human inflammation and immune response and playing a positive role through immune regulation [66]. In addition, the conversion of macrophages from a pro-inflammatory phenotype (M1) to an anti-inflammatory phenotype (M2) is crucial during the inflammatory and proliferation phase of wound healing. Multiple studies have found that the TLR4/NF-κB pathway is associated with enhanced M1 macrophage polarization promoting the production of ROS, TNF-α, IL-1β, and oxidative stress, significantly activating MAPKs and NF-κB pathways, while anti-inflammatory M2 macrophages inhibit NF-κB-mediated expression of inflammatory factors [67]. Other studies have shown that ADSC-Exos inhibit MIF and promote M1 to M2 macrophage polarization through miR-451a, thereby reducing inflammation and shortening the inflammatory phase of wound healing in diabetic wounds [68]. In addition, ADSCs release antimicrobial peptides (AMPs), which are effective and safe for combating bacterial, viral, and fungal infections, and can block the pro-inflammatory M1 macrophage response [69]. Furthermore, Yu et al. found that ADSC-CM can inhibit Propionibacterium acnes-induced NETosis [70].

Facilitating organizational reshaping and re-epithelialization

An essential indicator of wound healing is the remodeling of tissue and re-epithelialization, which forms a complete epidermal structure to restore the skin’s barrier function, thereby regulating the deposition and remodeling of ECM and improving late-stage scar formation. ADSC-EVs can promote the proliferation and migration of human dermal fibroblasts (HDF) and keratinocytes (HaCaT) via lncRNA MALAT-1 targeting miR-124 [71]. Furthermore, research indicates that ADSC-Exos can effectively inhibit ECM production in scar fibroblasts by suppressing the gene and protein expression of collagen I (COL-1), collagen III (COL-3), fibronectin (FN), and α-smooth muscle actin (α-SMA), as well as the TGF-β/Smad signaling pathway and Notch-1/Jagged-1 pathway, thereby promoting wound healing [72]. Additionally, the inhibition of scar proliferation can be significantly enhanced by the combination of ADSC-CM and in situ cross-linking of polysaccharide hydrogels [73].

The proper functioning of keratinocytes during re-epithelialization is crucial. The secreted proteome of PL-cultured ADSC contains more proteins, such as proliferative, differentiation or pro-angiogenic factors, which enhance keratinocyte movement and survival and improve wound healing [74]. In addition, epidermal stem cells from hair follicles can migrate to the wound site to differentiate into epidermal cells and contribute to re-epithelialization [75]. ADSC-EVs also contain VEGF and FGF, cytokines that stimulate follicle growth and activate the Wnt signaling pathway necessary for hair follicle induction [76]. Moreover, the stratum corneum (SC) is responsible for providing the epidermal barrier of the skin. It is composed of keratinocytes and a combination of intercellular lipids, including ceramides, free fatty acids, and cholesterol. ADSC-Exos effectively restore the function of the outermost layer of the skin in Atopic Dermatitis (AD) by stimulating the production of new ceramides [77].

Limitations and challenges in the clinical translation of ADSC secretome

The secretome of ADSCs has been well validated in the healing of DFU and other conditions, making it an ideal non-cellular therapy in regenerative medicine. According to data from ClinicalTrials.gov, the quantity of officially recorded clinical trials utilizing ADSC secretome as an intervention is increasing (see Table 2, available online at http://www.clinicaltrials.gov/, accessed July 8, 2024). However, the clinical translation of ADSC secretome continues to encounter significant challenges. First, the composition of secretome is highly variable due to differences in donors, tissue sources, culture conditions, extraction methods, and identification techniques. This variability complicates the precise determination of the secretome’s components and active ingredients. For instance, Kalinina et al. identified over 600 secreted proteins in the ADSC-CM using LC–MS [78], whereas Gregorio et al. identified 569 factors [44]. Additionally, Huang et al. demonstrated that varying isolation methods could alter the protein composition of exosomes [79]. Thus, accurately identifying the specific components of the secretome, efficiently extracting them, and eliminating irrelevant molecules are critical challenges that must be addressed. Moreover, successful clinical translation requires large-scale production while ensuring batch-to-batch consistency and reproducibility. Currently, there is no standardized protocol for the isolation and amplification of secretome components suitable for large-scale production. Furthermore, the method of administration, pharmacokinetics, and extension of the half-life of active ingredients present additional challenges for clinical translation. Lastly, Wang et al. discovered that ADSC-Exos could promote breast cancer cell growth by activating the Hippo signaling pathway [80]. The potential tumorigenic risks and immunogenicity associated with the use of biological products continue to be subjects of significant debate. In response to these concerns, a substantial number of in vivo and in vitro studies aim to address these challenges, focusing on pretreatment strategies and material phase aspects. It has been found that the biological activity of the secretome of ADSCs can be enhanced and wound healing can be promoted by physicochemical factors (e.g., hypoxia) [81], drugs (e.g., lipopolysaccharides, hydrogen peroxide) [82, 83], genetic engineering or inheritance (e.g., surface modification, genetic modification, and epigenetic reprogramming) [84], and by combining a variety of biomaterials (e.g., hydrogels,3D printed biomimetic scaffold) [85, 86]. Nevertheless, more systematic and extensive studies are needed to fully understand the specific components and mechanisms of action of the ADSC secretome and to facilitate its translation from the laboratory to clinical settings.Table 2 Clinical Trials of ADSC Secretome

NCT no	Title	Status	Conditions/disease	Interventions	Results	
NCT04544215	A Clinical Study of Mesenchymal Progenitor Cell Exosomes Nebulizer for the Treatment of Pulmonary Infection	Unknown	Drug resistant pulmonary infection	8 × 108 or 16 × 108 or no exosomes nano vesicles/3 mL per day for 7 days	N/A	
NCT05296863	Adipose-derived Stem Cell Conditioned Media as a Novel Approach for Hair Regrowth in Male Androgenetic Alopecia	Completed	Alopecia, Androgenetic Hair Loss/Baldness	2 ml intradermal injection of non- or concentrated ADSC-CM or Placebo + 1 ml of 5% topical Minoxidil daily	N/A	
NCT04276987	A Pilot Clinical Study on Inhalation of Mesenchymal Stem Cells Exosomes Treating Severe Novel Coronavirus Pneumonia	Completed	Coronavirus	Conventional treatment or 2 × 108 MSCs-derived exosomes /3 mL per day for 5 days	N/A	
NCT04223622	Effects of ASC Secretome on Human Osteochondral Explants	Recruiting	Osteoarthritis	The osteochondral explants isolated from arthroplasty patients will be induced to an OA phenotype and treated with ASC secretome (either complete conditioned medium or extracellular vesicles) in order to investigate its therapeutic potential	N/A	

Conclusion

DFU is a prevalent condition associated with diabetes, resulting from the combined effects of neuropathy, vascular disease, and infection. Increasing research indicates that the beneficial effects of ADSCs are primarily due to their paracrine actions, which promote tissue repair by mediating intercellular communication. The secretome of ADSCs includes various components such as cytokines, growth factors, proteins, lipids, mRNAs, microRNAs, lncRNAs, and DNA. These components, delivered via EVs and Exos, create an anti-inflammatory microenvironment that enhances diabetic wound healing. They also promote the proliferation and migration of M2 macrophages, endothelial cells, Schwann cells, fibroblasts, and keratinocytes, regulating inflammation and immune responses, promoting angiogenesis, improving neuropathy, facilitating tissue remodeling and re-epithelialization, and ultimately accelerating wound healing. Although extensive research and clinical trials are needed for clinical translation, the ADSC secretome holds promise for significant breakthroughs not only in chronic wound repair but also in other areas of regenerative medicine.

Abbreviations

DFUs Diabetes foot ulcers

ADSCs Adipose-derived stem cells

DM Diabetes mellitus

IWGDF The international working group on the diabetic foot

MSCs Mesenchymal stem cells

PKC Protein kinase C

AGEs Advanced glycation end products

ROS Reactive oxygen species

DRG Dorsal root ganglion

CXCR4 C-X-C chemokine receptor type 4

NF-κB Nuclear factor-kappa B

EPCs Endothelial progenitor cells

DFIs Diabetic foot infections

NETosis Neutrophil extracellular traps

TNFα Tumor necrosis factor-alpha

IL Interleukin

CD Cluster of differentiation

SASP Senescent-associated secretory profile

MMP-9 Matrix metalloproteinase-9

ECM Extracellular matrix

BMSCs Bone marrow mesenchymal stem cells

iPSCs Induced pluripotent stem cells

EVs Extracellular vesicles

ADSC-CM Adipose-derived stem cell conditioned medium (ADSC-CM)

MISEV2023 Minimal information for studies of extracellular vesicles 2023

apoVs Apoptotic vesicles

MVs Microvesicles

Exos Exosomes

VEGF Vascular endothelial growth factor

PDGF Platelet-derived growth factor

KGF Keratinocyte growth factor

EGF Epidermal growth factor

HGF Hepatocyte growth factor

bFGF Basic fibroblast growth factor

IGF Insulin-like growth factor

BDNF Brain-derived neurotrophic factor

GDNF Glial cell line-derived neurotrophic factor

NGF Nerve growth factor

HUVECs Human umbilical vein endothelial cells

IGFBP Insulin-like growth factor binding protein

MCP-1 Monocyte chemoattractant protein-1

GM-CSF Granulocyte-macrophage colony-stimulating factor

IFN-γ Interferon gamma

RANTES Regulated on activation, normal T cell expressed and secreted

CXCL C-X-C motif chemokine ligand

CCL CC Chemokine ligand

CX3CL1 C-X3-C motif chemokine ligand 1

XCL1 X-C motif chemokine ligand 1

CNTF Ciliary neurotrophic factor

NT Neurotrophin

miR MicroRNA

DNMT1 DNA (cytosine-5)-methyltransferase 1

NRF2 Nuclear factor erythroid 2-related factor 2

ACTA1 Actin, alpha 1, skeletal muscle

PI3K Phosphoinositide 3-kinase

AKT RAC-alpha serine/threonine-protein kinase

PTEN Phosphatase and tensin homolog

mTOR Mechanistic target of rapamycin

lncRNA Long non-coding RNA

SENCR Smooth muscle and endothelial cell-enriched migration/differentiation-associated long non-coding RNA

DKC1 Dyskerin pseudouridine synthase 1

EGR-1 Early growth response 1

SIRT3 Sirtuin 3

SOD2 Superoxide dismutase 2, mitochondrial

MAPKs Mitogen-activated protein kinases

AMPs Antimicrobial peptides

HDF Human dermal fibroblasts

HaCaT Keratinocytes

SC Stratum corneum

AD Atopic dermatitis

T cell T lymphocyte cell

B cell B lymphocyte cell

NK cell Natural killer cell

Acknowledgements

Not applicable. (The authors declare that they have not used Artificial Intelligence in this study.)

Author contributions

XW and XN conducted the literature review, collected data, authored the manuscript, and drafted the figures. BW and XS conceived the project and revised the manuscript. YX and LC edited the manuscript, while BC, QL, RK and TH designed the outline and also revised the manuscript. All authors have read and approved the final version of the manuscript.

Funding

This study was funded by Young and Middle-aged Key Personnel Training Project of Fujian Provincial Health Commission (No.2020GGB029); Joint Funds for the Innovation of Science and Technology, Fujian Province (No.2020Y9124); Natural Science Fundation of Fujian Province (No.2021J01244).

Availability of data and materials

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xiaofen Wan and Xuejun Ni contributed equally to this work.
==== Refs
References

1. Sun H Saeedi P Karuranga S Pinkepank M Ogurtsova K Duncan BB IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045 Diabetes Res Clin Pract 2022 183 109119 10.1016/j.diabres.2021.109119 34879977
Sun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. IDF Diabetes Atlas: global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:109119.34879977
2. Ji L Current challenges of diabetes and metabolic disorders in China Diabetes Obes Metab 2023 25 Suppl 1 3 4 10.1111/dom.15048 36880664
Ji L. Current challenges of diabetes and metabolic disorders in China. Diabetes Obes Metab. 2023;25(Suppl 1):3–4.36880664
3. McDermott K Fang M Boulton AJM Selvin E Hicks CW Etiology, epidemiology, and disparities in the burden of diabetic foot ulcers Diabetes Care 2023 46 1 209 221 10.2337/dci22-0043 36548709
McDermott K, Fang M, Boulton AJM, Selvin E, Hicks CW. Etiology, epidemiology, and disparities in the burden of diabetic foot ulcers. Diabetes Care. 2023;46(1):209–21.36548709
4. Perez-Favila A Martinez-Fierro ML Rodriguez-Lazalde JG Cid-Baez MA Zamudio-Osuna MJ Martinez-Blanco MDR Current therapeutic strategies in diabetic foot ulcers Med (Kaunas) 2019 55 11 714
Perez-Favila A, Martinez-Fierro ML, Rodriguez-Lazalde JG, Cid-Baez MA, Zamudio-Osuna MJ, Martinez-Blanco MDR, et al. Current therapeutic strategies in diabetic foot ulcers. Med (Kaunas). 2019;55(11):714.
5. Oyebode OA Jere SW Houreld NN Current therapeutic modalities for the management of chronic diabetic wounds of the foot J Diabetes Res 2023 2023 1359537 10.1155/2023/1359537 36818748
Oyebode OA, Jere SW, Houreld NN. Current therapeutic modalities for the management of chronic diabetic wounds of the foot. J Diabetes Res. 2023;2023:1359537.36818748
6. Chen P Vilorio NC Dhatariya K Jeffcoate W Lobmann R McIntosh C Guidelines on interventions to enhance healing of foot ulcers in people with diabetes (IWGDF 2023 update) Diabetes Metab Res Rev 2024 40 3 e3644 10.1002/dmrr.3644 37232034
Chen P, Vilorio NC, Dhatariya K, Jeffcoate W, Lobmann R, McIntosh C, et al. Guidelines on interventions to enhance healing of foot ulcers in people with diabetes (IWGDF 2023 update). Diabetes Metab Res Rev. 2024;40(3):e3644.37232034
7. Lazarus HM Haynesworth SE Gerson SL Rosenthal NS Caplan AI Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use Bone Marrow Transplant 1995 16 4 557 564 8528172
Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan AI. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant. 1995;16(4):557–64.8528172
8. Yuan T Meijia L Xinyao C Xinyue C Lijun H Exosome derived from human adipose-derived stem cell improve wound healing quality: a systematic review and meta-analysis of preclinical animal studies Int Wound J 2023 20 6 2424 2439 10.1111/iwj.14081 37102269
Yuan T, Meijia L, Xinyao C, Xinyue C, Lijun H. Exosome derived from human adipose-derived stem cell improve wound healing quality: a systematic review and meta-analysis of preclinical animal studies. Int Wound J. 2023;20(6):2424–39.37102269
9. Huayllani MT Sarabia-Estrada R Restrepo DJ Boczar D Sisti A Nguyen JH Adipose-derived stem cells in wound healing of full-thickness skin defects: a review of the literature() J Plast Surg Hand Surg 2020 54 5 263 279 10.1080/2000656X.2020.1767116 32427016
Huayllani MT, Sarabia-Estrada R, Restrepo DJ, Boczar D, Sisti A, Nguyen JH, et al. Adipose-derived stem cells in wound healing of full-thickness skin defects: a review of the literature(). J Plast Surg Hand Surg. 2020;54(5):263–79.32427016
10. Iacomi DM Rosca AM Tutuianu R Neagu TP Pruna V Simionescu M Generation of an immortalized human adipose-derived mesenchymal stromal cell line suitable for wound healing therapy Int J Mol Sci 2022 23 16 8925 10.3390/ijms23168925 36012192
Iacomi DM, Rosca AM, Tutuianu R, Neagu TP, Pruna V, Simionescu M, et al. Generation of an immortalized human adipose-derived mesenchymal stromal cell line suitable for wound healing therapy. Int J Mol Sci. 2022;23(16):8925.36012192
11. Ni X Shan X Xu L Yu W Zhang M Lei C Adipose-derived stem cells combined with platelet-rich plasma enhance wound healing in a rat model of full-thickness skin defects Stem Cell Res Ther 2021 12 1 226 10.1186/s13287-021-02257-1 33823915
Ni X, Shan X, Xu L, Yu W, Zhang M, Lei C, et al. Adipose-derived stem cells combined with platelet-rich plasma enhance wound healing in a rat model of full-thickness skin defects. Stem Cell Res Ther. 2021;12(1):226.33823915
12. Zhou Y Zhao B Zhang XL Lu YJ Lu ST Cheng J Combined topical and systemic administration with human adipose-derived mesenchymal stem cells (hADSC) and hADSC-derived exosomes markedly promoted cutaneous wound healing and regeneration Stem Cell Res Ther 2021 12 1 257 10.1186/s13287-021-02287-9 33933157
Zhou Y, Zhao B, Zhang XL, Lu YJ, Lu ST, Cheng J, et al. Combined topical and systemic administration with human adipose-derived mesenchymal stem cells (hADSC) and hADSC-derived exosomes markedly promoted cutaneous wound healing and regeneration. Stem Cell Res Ther. 2021;12(1):257.33933157
13. Singer AJ Healing mechanisms in cutaneous wounds: tipping the balance Tissue Eng Part B Rev 2022 28 5 1151 1167 10.1089/ten.teb.2021.0114 34915757
Singer AJ. Healing mechanisms in cutaneous wounds: tipping the balance. Tissue Eng Part B Rev. 2022;28(5):1151–67.34915757
14. Nowak NC Menichella DM Miller R Paller AS Cutaneous innervation in impaired diabetic wound healing Transl Res 2021 236 87 108 10.1016/j.trsl.2021.05.003 34029747
Nowak NC, Menichella DM, Miller R, Paller AS. Cutaneous innervation in impaired diabetic wound healing. Transl Res. 2021;236:87–108.34029747
15. Feldman EL Callaghan BC Pop-Busui R Zochodne DW Wright DE Bennett DL Diabetic neuropathy Nat Rev Dis Primers 2019 5 1 41 10.1038/s41572-019-0092-1 31197153
Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019;5(1):41.31197153
16. Armstrong DG Tan TW Boulton AJM Bus SA Diabetic foot ulcers: a review JAMA 2023 330 1 62 75 10.1001/jama.2023.10578 37395769
Armstrong DG, Tan TW, Boulton AJM, Bus SA. Diabetic foot ulcers: a review. JAMA. 2023;330(1):62–75.37395769
17. Armstrong DG Boulton AJM Bus SA Diabetic foot ulcers and their recurrence N Engl J Med 2017 376 24 2367 2375 10.1056/NEJMra1615439 28614678
Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376(24):2367–75.28614678
18. Feldman EL Nave KA Jensen TS Bennett DLH New horizons in diabetic neuropathy: mechanisms, bioenergetics, and pain Neuron 2017 93 6 1296 1313 10.1016/j.neuron.2017.02.005 28334605
Feldman EL, Nave KA, Jensen TS, Bennett DLH. New horizons in diabetic neuropathy: mechanisms, bioenergetics, and pain. Neuron. 2017;93(6):1296–313.28334605
19. Deng H Li B Shen Q Zhang C Kuang L Chen R Mechanisms of diabetic foot ulceration: a review J Diabetes 2023 15 4 299 312 10.1111/1753-0407.13372 36891783
Deng H, Li B, Shen Q, Zhang C, Kuang L, Chen R, et al. Mechanisms of diabetic foot ulceration: a review. J Diabetes. 2023;15(4):299–312.36891783
20. Nguyen DT Zaferanieh MH Black AC Jr Hamedi KR Goodwin RL Nathaniel TI Obstetric neuropathy in diabetic patients: the “double hit hypothesis” Int J Mol Sci. 2023 24 7 6812 10.3390/ijms24076812 37047786
Nguyen DT, Zaferanieh MH, Black AC Jr, Hamedi KR, Goodwin RL, Nathaniel TI. Obstetric neuropathy in diabetic patients: the “double hit hypothesis.” Int J Mol Sci. 2023;24(7):6812.37047786
21. Sharma S Schaper N Rayman G Microangiopathy: is it relevant to wound healing in diabetic foot disease? Diabetes Metab Res Rev 2020 36 Suppl 1 e3244 10.1002/dmrr.3244 31845461
Sharma S, Schaper N, Rayman G. Microangiopathy: is it relevant to wound healing in diabetic foot disease? Diabetes Metab Res Rev. 2020;36(Suppl 1): e3244.31845461
22. Schratzberger P Walter DH Rittig K Bahlmann FH Pola R Curry C Reversal of experimental diabetic neuropathy by VEGF gene transfer J Clin Invest 2001 107 9 1083 1092 10.1172/JCI12188 11342572
Schratzberger P, Walter DH, Rittig K, Bahlmann FH, Pola R, Curry C, et al. Reversal of experimental diabetic neuropathy by VEGF gene transfer. J Clin Invest. 2001;107(9):1083–92.11342572
23. Carmeliet P Jain RK Molecular mechanisms and clinical applications of angiogenesis Nature 2011 473 7347 298 307 10.1038/nature10144 21593862
Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307.21593862
24. Hristov M Erl W Weber PC Endothelial progenitor cells: mobilization, differentiation, and homing Arterioscler Thromb Vasc Biol 2003 23 7 1185 1189 10.1161/01.ATV.0000073832.49290.B5 12714439
Hristov M, Erl W, Weber PC. Endothelial progenitor cells: mobilization, differentiation, and homing. Arterioscler Thromb Vasc Biol. 2003;23(7):1185–9.12714439
25. Asahara T Murohara T Sullivan A Silver M van der Zee R Li T Isolation of putative progenitor endothelial cells for angiogenesis Science 1997 275 5302 964 967 10.1126/science.275.5302.964 9020076
Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275(5302):964–7.9020076
26. Pyšná A Bém R Němcová A Fejfarová V Jirkovská A Hazdrová J Endothelial progenitor cells biology in diabetes mellitus and peripheral arterial disease and their therapeutic potential Stem Cell Rev Rep 2019 15 2 157 165 10.1007/s12015-018-9863-4 30413930
Pyšná A, Bém R, Němcová A, Fejfarová V, Jirkovská A, Hazdrová J, et al. Endothelial progenitor cells biology in diabetes mellitus and peripheral arterial disease and their therapeutic potential. Stem Cell Rev Rep. 2019;15(2):157–65.30413930
27. Holt RIG Cockram CS Ma RCW Luk AOY Diabetes and infection: review of the epidemiology, mechanisms and principles of treatment Diabetologia 2024 67 7 1168 1180 10.1007/s00125-024-06102-x 38374451
Holt RIG, Cockram CS, Ma RCW, Luk AOY. Diabetes and infection: review of the epidemiology, mechanisms and principles of treatment. Diabetologia. 2024;67(7):1168–80.38374451
28. Radzieta M Sadeghpour-Heravi F Peters TJ Hu H Vickery K Jeffries T A multiomics approach to identify host-microbe alterations associated with infection severity in diabetic foot infections: a pilot study NPJ Biofilms Microbiomes 2021 7 1 29 10.1038/s41522-021-00202-x 33753735
Radzieta M, Sadeghpour-Heravi F, Peters TJ, Hu H, Vickery K, Jeffries T, et al. A multiomics approach to identify host-microbe alterations associated with infection severity in diabetic foot infections: a pilot study. NPJ Biofilms Microbiomes. 2021;7(1):29.33753735
29. Pouget C Dunyach-Remy C Pantel A Schuldiner S Sotto A Lavigne JP Biofilms in diabetic foot ulcers: significance and clinical relevance Microorganisms 2020 8 10 1580 10.3390/microorganisms8101580 33066595
Pouget C, Dunyach-Remy C, Pantel A, Schuldiner S, Sotto A, Lavigne JP. Biofilms in diabetic foot ulcers: significance and clinical relevance. Microorganisms. 2020;8(10):1580.33066595
30. Raja JM Maturana MA Kayali S Khouzam A Efeovbokhan N Diabetic foot ulcer: a comprehensive review of pathophysiology and management modalities World J Clin Cases 2023 11 8 1684 1693 10.12998/wjcc.v11.i8.1684 36970004
Raja JM, Maturana MA, Kayali S, Khouzam A, Efeovbokhan N. Diabetic foot ulcer: a comprehensive review of pathophysiology and management modalities. World J Clin Cases. 2023;11(8):1684–93.36970004
31. Cai Y Chen K Liu C Qu X Harnessing strategies for enhancing diabetic wound healing from the perspective of spatial inflammation patterns Bioact Mater 2023 28 243 254 37292231
Cai Y, Chen K, Liu C, Qu X. Harnessing strategies for enhancing diabetic wound healing from the perspective of spatial inflammation patterns. Bioact Mater. 2023;28:243–54.37292231
32. Pastar I Balukoff NC Marjanovic J Chen VY Stone RC Tomic-Canic M Molecular pathophysiology of chronic wounds: current state and future directions Cold Spring Harb Perspect Biol 2023 15 4 a041243 10.1101/cshperspect.a041243 36123031
Pastar I, Balukoff NC, Marjanovic J, Chen VY, Stone RC, Tomic-Canic M. Molecular pathophysiology of chronic wounds: current state and future directions. Cold Spring Harb Perspect Biol. 2023;15(4):a041243.36123031
33. Zhao X Chen J Sun H Zhang Y Zou D New insights into fibrosis from the ECM degradation perspective: the macrophage-MMP-ECM interaction Cell Biosci 2022 12 1 117 10.1186/s13578-022-00856-w 35897082
Zhao X, Chen J, Sun H, Zhang Y, Zou D. New insights into fibrosis from the ECM degradation perspective: the macrophage-MMP-ECM interaction. Cell Biosci. 2022;12(1):117.35897082
34. Zuk PA Zhu M Mizuno H Huang J Futrell JW Katz AJ Multilineage cells from human adipose tissue: implications for cell-based therapies Tissue Eng 2001 7 2 211 228 10.1089/107632701300062859 11304456
Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7(2):211–28.11304456
35. Trzyna A Banaś-Ząbczyk A Adipose-derived stem cells secretome and its potential application in “stem cell-free therapy” Biomolecules 2021 11 6 878 10.3390/biom11060878 34199330
Trzyna A, Banaś-Ząbczyk A. Adipose-derived stem cells secretome and its potential application in “stem cell-free therapy.” Biomolecules. 2021;11(6):878.34199330
36. Czerwiec K Zawrzykraj M Deptuła M Skoniecka A Tymińska A Zieliński J Adipose-derived mesenchymal stromal cells in basic research and clinical applications Int J Mol Sci 2023 24 4 3888 10.3390/ijms24043888 36835295
Czerwiec K, Zawrzykraj M, Deptuła M, Skoniecka A, Tymińska A, Zieliński J, et al. Adipose-derived mesenchymal stromal cells in basic research and clinical applications. Int J Mol Sci. 2023;24(4):3888.36835295
37. Yuan X Li L Liu H Luo J Zhao Y Pan C Strategies for improving adipose-derived stem cells for tissue regeneration Burns Trauma 2022 10 tkac028 10.1093/burnst/tkac028 35992369
Yuan X, Li L, Liu H, Luo J, Zhao Y, Pan C, et al. Strategies for improving adipose-derived stem cells for tissue regeneration. Burns Trauma. 2022;10:tkac028.35992369
38. Narsinh KH Jia F Robbins RC Kay MA Longaker MT Wu JC Generation of adult human induced pluripotent stem cells using nonviral minicircle DNA vectors Nat Protoc 2011 6 1 78 88 10.1038/nprot.2010.173 21212777
Narsinh KH, Jia F, Robbins RC, Kay MA, Longaker MT, Wu JC. Generation of adult human induced pluripotent stem cells using nonviral minicircle DNA vectors. Nat Protoc. 2011;6(1):78–88.21212777
39. Flamant S Loinard C Tamarat R MSC beneficial effects and limitations, and MSC-derived extracellular vesicles as a new cell-free therapy for tissue regeneration in irradiated condition Environ Adv 2023 13 100408 10.1016/j.envadv.2023.100408
Flamant S, Loinard C, Tamarat R. MSC beneficial effects and limitations, and MSC-derived extracellular vesicles as a new cell-free therapy for tissue regeneration in irradiated condition. Environ Adv. 2023;13:100408.
40. An YH Kim DH Lee EJ Lee D Park MJ Ko J High-efficient production of adipose-derived stem cell (ADSC) secretome through maturation process and its non-scarring wound healing applications Front Bioeng Biotechnol 2021 9 681501 10.3389/fbioe.2021.681501 34222219
An YH, Kim DH, Lee EJ, Lee D, Park MJ, Ko J, et al. High-efficient production of adipose-derived stem cell (ADSC) secretome through maturation process and its non-scarring wound healing applications. Front Bioeng Biotechnol. 2021;9:681501.34222219
41. Tjalsma H Bolhuis A Jongbloed JD Bron S van Dijl JM Signal peptide-dependent protein transport in Bacillus subtilis: a genome-based survey of the secretome Microbiol Mol Biol Rev 2000 64 3 515 547 10.1128/MMBR.64.3.515-547.2000 10974125
Tjalsma H, Bolhuis A, Jongbloed JD, Bron S, van Dijl JM. Signal peptide-dependent protein transport in Bacillus subtilis: a genome-based survey of the secretome. Microbiol Mol Biol Rev. 2000;64(3):515–47.10974125
42. Ajit A Ambika GI Adipose-derived stem cell secretome as a cell-free product for cutaneous wound healing 3 Biotech 2021 11 9 413 10.1007/s13205-021-02958-7 34476171
Ajit A, Ambika GI. Adipose-derived stem cell secretome as a cell-free product for cutaneous wound healing. 3 Biotech. 2021;11(9):413.34476171
43. Kumar L Kandoi S Misra R Vijayalakshmi S Rajagopal K Verma RS The mesenchymal stem cell secretome: a new paradigm towards cell-free therapeutic mode in regenerative medicine Cytokine Growth Factor Rev 2019 46 1 9 10.1016/j.cytogfr.2019.04.002 30954374
Kumar L, Kandoi S, Misra R, Vijayalakshmi S, Rajagopal K, Verma RS. The mesenchymal stem cell secretome: a new paradigm towards cell-free therapeutic mode in regenerative medicine. Cytokine Growth Factor Rev. 2019;46:1–9.30954374
44. De Gregorio C Contador D Díaz D Cárcamo C Santapau D Lobos-Gonzalez L Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice Stem Cell Res Ther 2020 11 1 168 10.1186/s13287-020-01680-0 32357914
De Gregorio C, Contador D, Díaz D, Cárcamo C, Santapau D, Lobos-Gonzalez L, et al. Human adipose-derived mesenchymal stem cell-conditioned medium ameliorates polyneuropathy and foot ulceration in diabetic BKS db/db mice. Stem Cell Res Ther. 2020;11(1):168.32357914
45. Bormann D Gugerell A Ankersmit HJ Mildner M Therapeutic application of cell secretomes in cutaneous wound healing J Invest Dermatol 2023 143 6 893 912 10.1016/j.jid.2023.02.019 37211377
Bormann D, Gugerell A, Ankersmit HJ, Mildner M. Therapeutic application of cell secretomes in cutaneous wound healing. J Invest Dermatol. 2023;143(6):893–912.37211377
46. Welsh JA Goberdhan DCI O’Driscoll L Buzas EI Blenkiron C Bussolati B Minimal information for studies of extracellular vesicles (MISEV2023): from basic to advanced approaches J Extracell Vesicles 2024 13 2 e12404 10.1002/jev2.12404 38326288
Welsh JA, Goberdhan DCI, O’Driscoll L, Buzas EI, Blenkiron C, Bussolati B, et al. Minimal information for studies of extracellular vesicles (MISEV2023): from basic to advanced approaches. J Extracell Vesicles. 2024;13(2):e12404.38326288
47. Ding JY Chen MJ Wu LF Shu GF Fang SJ Li ZY Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges Mil Med Res 2023 10 1 36 37587531
Ding JY, Chen MJ, Wu LF, Shu GF, Fang SJ, Li ZY, et al. Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges. Mil Med Res. 2023;10(1):36.37587531
48. Hade MD Suire CN Mossell J Suo Z Extracellular vesicles: emerging frontiers in wound healing Med Res Rev 2022 42 6 2102 2125 10.1002/med.21918 35757979
Hade MD, Suire CN, Mossell J, Suo Z. Extracellular vesicles: emerging frontiers in wound healing. Med Res Rev. 2022;42(6):2102–25.35757979
49. Ma L Li Y Peng J Wu D Zhao X Cui Y Discovery of the migrasome, an organelle mediating release of cytoplasmic contents during cell migration Cell Res 2015 25 1 24 38 10.1038/cr.2014.135 25342562
Ma L, Li Y, Peng J, Wu D, Zhao X, Cui Y, et al. Discovery of the migrasome, an organelle mediating release of cytoplasmic contents during cell migration. Cell Res. 2015;25(1):24–38.25342562
50. Jiao H Li X Li Y Guo Y Hu X Sho T Localized, highly efficient secretion of signaling proteins by migrasomes Cell Res 2024 34 8 572 585 10.1038/s41422-024-00992-7 38918584
Jiao H, Li X, Li Y, Guo Y, Hu X, Sho T, et al. Localized, highly efficient secretion of signaling proteins by migrasomes. Cell Res. 2024;34(8):572–85.38918584
51. Cai Y Li J Jia C He Y Deng C Therapeutic applications of adipose cell-free derivatives: a review Stem Cell Res Ther 2020 11 1 312 10.1186/s13287-020-01831-3 32698868
Cai Y, Li J, Jia C, He Y, Deng C. Therapeutic applications of adipose cell-free derivatives: a review. Stem Cell Res Ther. 2020;11(1):312.32698868
52. Rau CS Kuo PJ Wu SC Huang LH Lu TH Wu YC Enhanced nerve regeneration by exosomes secreted by adipose-derived stem cells with or without FK506 stimulation Int J Mol Sci 2021 22 16 8545 10.3390/ijms22168545 34445251
Rau CS, Kuo PJ, Wu SC, Huang LH, Lu TH, Wu YC, et al. Enhanced nerve regeneration by exosomes secreted by adipose-derived stem cells with or without FK506 stimulation. Int J Mol Sci. 2021;22(16):8545.34445251
53. Chen J Li G Liu X Chen K Wang Y Qin J Delivery of miR-130a-3p through adipose-derived stem cell-secreted EVs protects against diabetic peripheral neuropathy via DNMT1/NRF2/HIF1α/ACTA1 Axis Mol Neurobiol 2023 60 7 3678 3694 10.1007/s12035-023-03297-9 36933145
Chen J, Li G, Liu X, Chen K, Wang Y, Qin J, et al. Delivery of miR-130a-3p through adipose-derived stem cell-secreted EVs protects against diabetic peripheral neuropathy via DNMT1/NRF2/HIF1α/ACTA1 Axis. Mol Neurobiol. 2023;60(7):3678–94.36933145
54. Yin G Yu B Liu C Lin Y Xie Z Hu Y Exosomes produced by adipose-derived stem cells inhibit schwann cells autophagy and promote the regeneration of the myelin sheath Int J Biochem Cell Biol 2021 132 105921 10.1016/j.biocel.2021.105921 33421632
Yin G, Yu B, Liu C, Lin Y, Xie Z, Hu Y, et al. Exosomes produced by adipose-derived stem cells inhibit schwann cells autophagy and promote the regeneration of the myelin sheath. Int J Biochem Cell Biol. 2021;132:105921.33421632
55. Pi L Yang L Fang BR Meng XX Qian L Exosomal microRNA-125a-3p from human adipose-derived mesenchymal stem cells promotes angiogenesis of wound healing through inhibiting PTEN Mol Cell Biochem 2022 477 1 115 127 10.1007/s11010-021-04251-w 34581942
Pi L, Yang L, Fang BR, Meng XX, Qian L. Exosomal microRNA-125a-3p from human adipose-derived mesenchymal stem cells promotes angiogenesis of wound healing through inhibiting PTEN. Mol Cell Biochem. 2022;477(1):115–27.34581942
56. Ma J Zhang Z Wang Y Shen H Investigation of miR-126-3p loaded on adipose stem cell-derived exosomes for wound healing of full-thickness skin defects Exp Dermatol 2022 31 3 362 374 10.1111/exd.14480 34694648
Ma J, Zhang Z, Wang Y, Shen H. Investigation of miR-126-3p loaded on adipose stem cell-derived exosomes for wound healing of full-thickness skin defects. Exp Dermatol. 2022;31(3):362–74.34694648
57. Shi R Jin Y Hu W Lian W Cao C Han S Exosomes derived from mmu_circ_0000250-modified adipose-derived mesenchymal stem cells promote wound healing in diabetic mice by inducing miR-128-3p/SIRT1-mediated autophagy Am J Physiol Cell Physiol 2020 318 5 C848 C856 10.1152/ajpcell.00041.2020 32159361
Shi R, Jin Y, Hu W, Lian W, Cao C, Han S, et al. Exosomes derived from mmu_circ_0000250-modified adipose-derived mesenchymal stem cells promote wound healing in diabetic mice by inducing miR-128-3p/SIRT1-mediated autophagy. Am J Physiol Cell Physiol. 2020;318(5):C848–56.32159361
58. Zhu LL Huang X Yu W Chen H Chen Y Dai YT Transplantation of adipose tissue-derived stem cell-derived exosomes ameliorates erectile function in diabetic rats Andrologia 2018 50 2 e12871 10.1111/and.12871
Zhu LL, Huang X, Yu W, Chen H, Chen Y, Dai YT. Transplantation of adipose tissue-derived stem cell-derived exosomes ameliorates erectile function in diabetic rats. Andrologia. 2018;50(2):e12871.
59. Rehman J Traktuev D Li J Merfeld-Clauss S Temm-Grove CJ Bovenkerk JE Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells Circulation 2004 109 10 1292 1298 10.1161/01.CIR.0000121425.42966.F1 14993122
Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, Bovenkerk JE, et al. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation. 2004;109(10):1292–8.14993122
60. Sun D Mou S Chen L Yang J Wang R Zhong A High yield engineered nanovesicles from ADSC with enriched miR-21-5p promote angiogenesis in adipose tissue regeneration Biomater Res 2022 26 1 83 10.1186/s40824-022-00325-y 36528594
Sun D, Mou S, Chen L, Yang J, Wang R, Zhong A, et al. High yield engineered nanovesicles from ADSC with enriched miR-21-5p promote angiogenesis in adipose tissue regeneration. Biomater Res. 2022;26(1):83.36528594
61. Sun Y Ju Y Fang B Exosomes from human adipose-derived mesenchymal stromal/stem cells accelerate angiogenesis in wound healing: implication of the EGR-1/lncRNA-SENCR/DKC1/VEGF-A axis Hum Cell 2022 35 5 1375 1390 10.1007/s13577-022-00732-2 35751795
Sun Y, Ju Y, Fang B. Exosomes from human adipose-derived mesenchymal stromal/stem cells accelerate angiogenesis in wound healing: implication of the EGR-1/lncRNA-SENCR/DKC1/VEGF-A axis. Hum Cell. 2022;35(5):1375–90.35751795
62. Zhang Y Bai X Shen K Luo L Zhao M Xu C Exosomes derived from adipose mesenchymal stem cells promote diabetic chronic wound healing through SIRT3/SOD2 Cells 2022 11 16 2568 10.3390/cells11162568 36010644
Zhang Y, Bai X, Shen K, Luo L, Zhao M, Xu C, et al. Exosomes derived from adipose mesenchymal stem cells promote diabetic chronic wound healing through SIRT3/SOD2. Cells. 2022;11(16):2568.36010644
63. Li X Xie X Lian W Shi R Han S Zhang H Exosomes from adipose-derived stem cells overexpressing Nrf2 accelerate cutaneous wound healing by promoting vascularization in a diabetic foot ulcer rat model Exp Mol Med 2018 50 4 1 14 10.1038/s12276-018-0058-5 30559383
Li X, Xie X, Lian W, Shi R, Han S, Zhang H, et al. Exosomes from adipose-derived stem cells overexpressing Nrf2 accelerate cutaneous wound healing by promoting vascularization in a diabetic foot ulcer rat model. Exp Mol Med. 2018;50(4):1–14.30559383
64. Deniz IA Karbanová J Wobus M Bornhäuser M Wimberger P Kuhlmann JD Mesenchymal stromal cell-associated migrasomes: a new source of chemoattractant for cells of hematopoietic origin Cell Commun Signal 2023 21 1 36 10.1186/s12964-022-01028-6 36788616
Deniz IA, Karbanová J, Wobus M, Bornhäuser M, Wimberger P, Kuhlmann JD, et al. Mesenchymal stromal cell-associated migrasomes: a new source of chemoattractant for cells of hematopoietic origin. Cell Commun Signal. 2023;21(1):36.36788616
65. Zhang Y Zhang YY Pan ZW Li QQ Sun LH Li X GDF11 promotes wound healing in diabetic mice via stimulating HIF-1ɑ-VEGF/SDF-1ɑ-mediated endothelial progenitor cell mobilization and neovascularization Acta Pharmacol Sin 2023 44 5 999 1013 10.1038/s41401-022-01013-2 36347996
Zhang Y, Zhang YY, Pan ZW, Li QQ, Sun LH, Li X, et al. GDF11 promotes wound healing in diabetic mice via stimulating HIF-1ɑ-VEGF/SDF-1ɑ-mediated endothelial progenitor cell mobilization and neovascularization. Acta Pharmacol Sin. 2023;44(5):999–1013.36347996
66. Blazquez R Sanchez-Margallo FM de la Rosa O Dalemans W Alvarez V Tarazona R Immunomodulatory potential of human adipose mesenchymal stem cells derived exosomes on in vitro stimulated T cells Front Immunol 2014 5 556 10.3389/fimmu.2014.00556 25414703
Blazquez R, Sanchez-Margallo FM, de la Rosa O, Dalemans W, Alvarez V, Tarazona R, et al. Immunomodulatory potential of human adipose mesenchymal stem cells derived exosomes on in vitro stimulated T cells. Front Immunol. 2014;5:556.25414703
67. Franz S Ertel A Engel KM Simon JC Saalbach A Overexpression of S100A9 in obesity impairs macrophage differentiation via TLR4-NFkB-signaling worsening inflammation and wound healing Theranostics 2022 12 4 1659 1682 10.7150/thno.67174 35198063
Franz S, Ertel A, Engel KM, Simon JC, Saalbach A. Overexpression of S100A9 in obesity impairs macrophage differentiation via TLR4-NFkB-signaling worsening inflammation and wound healing. Theranostics. 2022;12(4):1659–82.35198063
68. Li R Li D Wang H Chen K Wang S Xu J Exosomes from adipose-derived stem cells regulate M1/M2 macrophage phenotypic polarization to promote bone healing via miR-451a/MIF Stem Cell Res Ther 2022 13 1 149 10.1186/s13287-022-02823-1 35395782
Li R, Li D, Wang H, Chen K, Wang S, Xu J, et al. Exosomes from adipose-derived stem cells regulate M1/M2 macrophage phenotypic polarization to promote bone healing via miR-451a/MIF. Stem Cell Res Ther. 2022;13(1):149.35395782
69. Maguire G The safe and efficacious use of secretome from fibroblasts and adipose-derived (but not bone marrow-derived) mesenchymal stem cells for skin therapeutics J Clin Aesthet Dermatol 2019 12 8 E57 e69 31531174
Maguire G. The safe and efficacious use of secretome from fibroblasts and adipose-derived (but not bone marrow-derived) mesenchymal stem cells for skin therapeutics. J Clin Aesthet Dermatol. 2019;12(8):E57-e69.31531174
70. Yu H Zhang B Zhan Y Yi Y Jiang Q Zhang Q Neutrophil extracellular trap-related mechanisms in acne vulgaris inspire a novel treatment strategy with adipose-derived stem cells Sci Rep 2024 14 1 1521 10.1038/s41598-024-51931-w 38233540
Yu H, Zhang B, Zhan Y, Yi Y, Jiang Q, Zhang Q, et al. Neutrophil extracellular trap-related mechanisms in acne vulgaris inspire a novel treatment strategy with adipose-derived stem cells. Sci Rep. 2024;14(1):1521.38233540
71. He L Zhu C Jia J Hao XY Yu XY Liu XY 2020 ADSC-Exos containing MALAT1 promotes wound healing by targeting miR-124 through activating Wnt/β-catenin pathway Biosci Rep 10.1042/BSR20192549
He L, Zhu C, Jia J, Hao XY, Yu XY, Liu XY, et al. ADSC-Exos containing MALAT1 promotes wound healing by targeting miR-124 through activating Wnt/β-catenin pathway. 2020. Biosci Rep. 10.1042/BSR20192549.
72. Li J Li Z Wang S Bi J Huo R Exosomes from human adipose-derived mesenchymal stem cells inhibit production of extracellular matrix in keloid fibroblasts via downregulating transforming growth factor-β2 and Notch-1 expression Bioengineered 2022 13 4 8515 8525 10.1080/21655979.2022.2051838 35333672
Li J, Li Z, Wang S, Bi J, Huo R. Exosomes from human adipose-derived mesenchymal stem cells inhibit production of extracellular matrix in keloid fibroblasts via downregulating transforming growth factor-β2 and Notch-1 expression. Bioengineered. 2022;13(4):8515–25.35333672
73. Zhang C Wang T Zhang L Chen P Tang S Chen A Combination of lyophilized adipose-derived stem cell concentrated conditioned medium and polysaccharide hydrogel in the inhibition of hypertrophic scarring Stem Cell Res Ther 2021 12 1 23 10.1186/s13287-020-02061-3 33413617
Zhang C, Wang T, Zhang L, Chen P, Tang S, Chen A, et al. Combination of lyophilized adipose-derived stem cell concentrated conditioned medium and polysaccharide hydrogel in the inhibition of hypertrophic scarring. Stem Cell Res Ther. 2021;12(1):23.33413617
74. Hermann M Peddi A Gerhards A Schmid R Schmitz D Arkudas A Secretome of adipose-derived stem cells cultured in platelet lysate improves migration and viability of keratinocytes Int J Mol Sci. 2023 24 4 3522 10.3390/ijms24043522 36834932
Hermann M, Peddi A, Gerhards A, Schmid R, Schmitz D, Arkudas A, et al. Secretome of adipose-derived stem cells cultured in platelet lysate improves migration and viability of keratinocytes. Int J Mol Sci. 2023;24(4):3522.36834932
75. Nuutila K Hair follicle transplantation for wound repair Adv Wound Care (New Rochelle) 2021 10 3 153 163 10.1089/wound.2019.1139 32522101
Nuutila K. Hair follicle transplantation for wound repair. Adv Wound Care (New Rochelle). 2021;10(3):153–63.32522101
76. Wang Y Cheng L Zhao H Li Z Chen J Cen Y The Therapeutic role of ADSC-EVs in skin regeneration Front Med (Lausanne) 2022 9 858824 10.3389/fmed.2022.858824 35755023
Wang Y, Cheng L, Zhao H, Li Z, Chen J, Cen Y, et al. The Therapeutic role of ADSC-EVs in skin regeneration. Front Med (Lausanne). 2022;9:858824.35755023
77. Shin KO Ha DH Kim JO Crumrine DA Meyer JM Wakefield JS Exosomes from human adipose tissue-derived mesenchymal stem cells promote epidermal barrier repair by inducing de novo synthesis of ceramides in atopic dermatitis Cells 2020 9 3 680 10.3390/cells9030680 32164386
Shin KO, Ha DH, Kim JO, Crumrine DA, Meyer JM, Wakefield JS, et al. Exosomes from human adipose tissue-derived mesenchymal stem cells promote epidermal barrier repair by inducing de novo synthesis of ceramides in atopic dermatitis. Cells. 2020;9(3):680.32164386
78. Kalinina N Kharlampieva D Loguinova M Butenko I Pobeguts O Efimenko A Characterization of secretomes provides evidence for adipose-derived mesenchymal stromal cells subtypes Stem Cell Res Ther 2015 6 221 10.1186/s13287-015-0209-8 26560317
Kalinina N, Kharlampieva D, Loguinova M, Butenko I, Pobeguts O, Efimenko A, et al. Characterization of secretomes provides evidence for adipose-derived mesenchymal stromal cells subtypes. Stem Cell Res Ther. 2015;6:221.26560317
79. Huang LH Rau CS Wu SC Wu YC Wu CJ Tsai CW Identification and characterization of hADSC-derived exosome proteins from different isolation methods J Cell Mol Med 2021 25 15 7436 7450 10.1111/jcmm.16775 34235869
Huang LH, Rau CS, Wu SC, Wu YC, Wu CJ, Tsai CW, et al. Identification and characterization of hADSC-derived exosome proteins from different isolation methods. J Cell Mol Med. 2021;25(15):7436–50.34235869
80. Wang S Su X Xu M Xiao X Li X Li H Exosomes secreted by mesenchymal stromal/stem cell-derived adipocytes promote breast cancer cell growth via activation of Hippo signaling pathway Stem Cell Res Ther 2019 10 1 117 10.1186/s13287-019-1220-2 30971292
Wang S, Su X, Xu M, Xiao X, Li X, Li H, et al. Exosomes secreted by mesenchymal stromal/stem cell-derived adipocytes promote breast cancer cell growth via activation of Hippo signaling pathway. Stem Cell Res Ther. 2019;10(1):117.30971292
81. Qian L Li B Pi L Fang B Meng X Hypoxic adipose stem cell-derived exosomes carrying high-abundant USP22 facilitate cutaneous wound healing through stabilizing HIF-1α and upregulating lncRNA H19 Faseb j 2024 38 10 e23653 10.1096/fj.202301403RR 38738548
Qian L, Li B, Pi L, Fang B, Meng X. Hypoxic adipose stem cell-derived exosomes carrying high-abundant USP22 facilitate cutaneous wound healing through stabilizing HIF-1α and upregulating lncRNA H19. Faseb j. 2024;38(10):e23653.38738548
82. Ti D Hao H Tong C Liu J Dong L Zheng J LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b J Transl Med 2015 13 308 10.1186/s12967-015-0642-6 26386558
Ti D, Hao H, Tong C, Liu J, Dong L, Zheng J, et al. LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b. J Transl Med. 2015;13:308.26386558
83. Bai Y Han YD Yan XL Ren J Zeng Q Li XD Adipose mesenchymal stem cell-derived exosomes stimulated by hydrogen peroxide enhanced skin flap recovery in ischemia-reperfusion injury Biochem Biophys Res Commun 2018 500 2 310 317 10.1016/j.bbrc.2018.04.065 29654765
Bai Y, Han YD, Yan XL, Ren J, Zeng Q, Li XD, et al. Adipose mesenchymal stem cell-derived exosomes stimulated by hydrogen peroxide enhanced skin flap recovery in ischemia-reperfusion injury. Biochem Biophys Res Commun. 2018;500(2):310–7.29654765
84. Yu H Wu Y Zhang B Xiong M Yi Y Zhang Q Exosomes derived from E2F1(-/-) adipose-derived stem cells promote skin wound healing via miR-130b-5p/TGFBR3 Axis Int J Nanomedicine 2023 18 6275 6292 10.2147/IJN.S431725 37941530
Yu H, Wu Y, Zhang B, Xiong M, Yi Y, Zhang Q, et al. Exosomes derived from E2F1(-/-) adipose-derived stem cells promote skin wound healing via miR-130b-5p/TGFBR3 Axis. Int J Nanomedicine. 2023;18:6275–92.37941530
85. Ju Y Hu Y Yang P Xie X Fang B Extracellular vesicle-loaded hydrogels for tissue repair and regeneration Mater Today Bio 2023 18 100522 10.1016/j.mtbio.2022.100522 36593913
Ju Y, Hu Y, Yang P, Xie X, Fang B. Extracellular vesicle-loaded hydrogels for tissue repair and regeneration. Mater Today Bio. 2023;18:100522.36593913
86. Jiang W Zhan Y Zhang Y Sun D Zhang G Wang Z Synergistic large segmental bone repair by 3D printed bionic scaffolds and engineered ADSC nanovesicles: Towards an optimized regenerative microenvironment Biomaterials 2024 308 122566 10.1016/j.biomaterials.2024.122566 38603824
Jiang W, Zhan Y, Zhang Y, Sun D, Zhang G, Wang Z, et al. Synergistic large segmental bone repair by 3D printed bionic scaffolds and engineered ADSC nanovesicles: Towards an optimized regenerative microenvironment. Biomaterials. 2024;308:122566.38603824
87. Park BS Kim WS Choi JS Kim HK Won JH Ohkubo F Hair growth stimulated by conditioned medium of adipose-derived stem cells is enhanced by hypoxia: evidence of increased growth factor secretion Biomed Res 2010 31 1 27 34 10.2220/biomedres.31.27 20203417
Park BS, Kim WS, Choi JS, Kim HK, Won JH, Ohkubo F, et al. Hair growth stimulated by conditioned medium of adipose-derived stem cells is enhanced by hypoxia: evidence of increased growth factor secretion. Biomed Res. 2010;31(1):27–34.20203417
88. Edmondson SR Thumiger SP Werther GA Wraight CJ Epidermal homeostasis: the role of the growth hormone and insulin-like growth factor systems Endocr Rev 2003 24 6 737 764 10.1210/er.2002-0021 14671001
Edmondson SR, Thumiger SP, Werther GA, Wraight CJ. Epidermal homeostasis: the role of the growth hormone and insulin-like growth factor systems. Endocr Rev. 2003;24(6):737–64.14671001
89. Leone A Nicolò A Prevenzano I Zatterale F Longo M Desiderio A Methylglyoxal impairs the pro-angiogenic ability of mouse adipose-derived stem cells (mADSCs) via a senescence-associated mechanism Cells 2023 12 13 1741 10.3390/cells12131741 37443775
Leone A, Nicolò A, Prevenzano I, Zatterale F, Longo M, Desiderio A, et al. Methylglyoxal impairs the pro-angiogenic ability of mouse adipose-derived stem cells (mADSCs) via a senescence-associated mechanism. Cells. 2023;12(13):1741.37443775
90. Wiśniewska J Słyszewska M Stałanowska K Walendzik K Kopcewicz M Machcińska S Effect of pig-adipose-derived stem cells’ conditioned media on skin wound-healing characteristics in vitro Int J Mol Sci 2021 22 11 5469 10.3390/ijms22115469 34067360
Wiśniewska J, Słyszewska M, Stałanowska K, Walendzik K, Kopcewicz M, Machcińska S, et al. Effect of pig-adipose-derived stem cells’ conditioned media on skin wound-healing characteristics in vitro. Int J Mol Sci. 2021;22(11):5469.34067360
91. Wang L Li H Lin J He R Chen M Zhang Y CCR2 improves homing and engraftment of adipose-derived stem cells in dystrophic mice Stem Cell Res Ther 2021 12 1 12 10.1186/s13287-020-02065-z 33413615
Wang L, Li H, Lin J, He R, Chen M, Zhang Y, et al. CCR2 improves homing and engraftment of adipose-derived stem cells in dystrophic mice. Stem Cell Res Ther. 2021;12(1):12.33413615
92. Zhang H Ning H Banie L Wang G Lin G Lue TF Adipose tissue-derived stem cells secrete CXCL5 cytokine with chemoattractant and angiogenic properties Biochem Biophys Res Commun 2010 402 3 560 564 10.1016/j.bbrc.2010.10.090 21034724
Zhang H, Ning H, Banie L, Wang G, Lin G, Lue TF, et al. Adipose tissue-derived stem cells secrete CXCL5 cytokine with chemoattractant and angiogenic properties. Biochem Biophys Res Commun. 2010;402(3):560–4.21034724
93. Wang WT Lee SS Wang YC Lai YW Kuo YR Tang Chen YB Impaired cutaneous T-cell attracting chemokine elevation and adipose-derived stromal cell migration in a high-glucose environment cause poor diabetic wound healing Kaohsiung J Med Sci 2018 34 10 539 546 10.1016/j.kjms.2018.05.002 30309481
Wang WT, Lee SS, Wang YC, Lai YW, Kuo YR, Tang Chen YB, et al. Impaired cutaneous T-cell attracting chemokine elevation and adipose-derived stromal cell migration in a high-glucose environment cause poor diabetic wound healing. Kaohsiung J Med Sci. 2018;34(10):539–46.30309481
94. Bhang SH Lee S Shin JY Lee TJ Jang HK Kim BS Efficacious and clinically relevant conditioned medium of human adipose-derived stem cells for therapeutic angiogenesis Mol Ther 2014 22 4 862 872 10.1038/mt.2013.301 24413377
Bhang SH, Lee S, Shin JY, Lee TJ, Jang HK, Kim BS. Efficacious and clinically relevant conditioned medium of human adipose-derived stem cells for therapeutic angiogenesis. Mol Ther. 2014;22(4):862–72.24413377
