
==== Front
Dement Neuropsychol
dn
Dementia & Neuropsychologia
1980-5764
2764-4863
Academia Brasileira de Neurologia, Departamento de Neurologia Cognitiva e Envelhecimento

10.1590/1980-5764-DN-2024-0147
00214
View and Review
A systematic review of clinical efficacy and safety of cell-based therapies in Alzheimer’s disease
Uma revisão sistemática da eficácia clínica e segurança das terapias baseadas em células na doença de Alzheimerhttp://orcid.org/0000-0001-5869-1738
Feizi Hamidreza 1 investigation resources
http://orcid.org/0000-0003-2765-5018
Hosseini Mohammad-Salar 2 3 investigation resources writing – review editing
http://orcid.org/0000-0002-2623-226X
Seyedi-Sahebari Sepideh 1 investigation resources
http://orcid.org/0000-0001-9941-0437
Karimi Hanie 4 funding-acquisition investigation project administration resources writing – original draft
http://orcid.org/0000-0002-3353-1102
Mosaddeghi-Heris Reza 5 funding-acquisition investigation project administration resources writing – original draft
http://orcid.org/0000-0003-2872-1072
Sadigh-Eteghad Saeed 5 methodology writing – review & editing
http://orcid.org/0000-0001-9446-9763
Sadeghi-Ghyassi Fatemeh 3 methodology
http://orcid.org/0000-0002-7613-3913
Talebi Mahnaz 5 conceptualization funding acquisition supervision validation writing – review & editing
http://orcid.org/0000-0001-9723-0109
Naseri Amirreza 1 3 6 funding acquisition investigation project administration resources writing – original draft
http://orcid.org/0000-0001-9030-2106
Salehi-Pourmehr Hanieh 3 7 methodology writing – review & editing
http://orcid.org/0000-0001-5329-0951
Roshangar Leila 8 methodology writing – review & editing
1 Tabriz University of Medical Sciences, Student Research Committee, Tabriz, Iran. Tabriz University of Medical Sciences Student Research Committee Tabriz Iran
2 Tabriz University of Medical Sciences, Aging Research Institute, Research Center for Integrative Medicine in Aging, Tabriz, Iran. Tabriz University of Medical Sciences Aging Research Institute Research Center for Integrative Medicine in Aging Tabriz Iran
3 Tabriz University of Medical Sciences, Research Center for Evidence-Based Medicine, Iranian EBM Centre: JBI Centre of Excellence, Faculty of Medicine, Tabriz, Iran. Tabriz University of Medical Sciences Research Center for Evidence-Based Medicine Iranian EBM Centre: JBI Centre of Excellence, Faculty of Medicine Tabriz Iran
4 Tehran University of Medical Sciences, School of Medicine, Tehran, Iran. Tehran University of Medical Sciences School of Medicine Tabriz Iran
5 Tabriz University of Medical Sciences, Neuroscience Research Center, Tabriz, Iran. Tabriz University of Medical Sciences Neuroscience Research Center Tabriz Iran
6 Tabriz University of Medical Sciences, Tabriz Valiasr Hospital, Clinical Research Development Unit, Tabriz, Iran. Tabriz University of Medical Sciences Tabriz Valiasr Hospital Clinical Research Development Unit Tabriz Iran
7 Tabriz University of Medical Sciences, Medical Philosophy and History Research Center, Tabriz, Iran. Tabriz University of Medical Sciences Medical Philosophy and History Research Center Tabriz Iran
8 Tabriz University of Medical Sciences, Stem Cell Research Center, Tabriz, Iran. Tabriz University of Medical Sciences Stem Cell Research Center Tabriz Iran
Correspondence: Hanieh Salehi-Pourmehr; Email: salehiha@tbzmed.ac.ir.
This study was conducted by the Student Research Committee of Tabriz University of Medical Sciences.

Disclosure: The authors report no conflicts of interest.

06 9 2024
2024
18 e2024014714 4 2024
22 4 2024
https://creativecommons.org/licenses/by/4.0/ This is an article published in open access under a Creative Commons license.
ABSTRACT

There is presently no disease-modifying therapy for Alzheimer’s Disease (AD), which is the most prevalent cause of dementia.

Objective:

This study aspires to estimate the efficacy and safety of cell-based treatments in AD.

Methods:

Observing the Joanna Briggs Institute (JBI) methods and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, a systematic search was accomplished in PubMed, Medical Literature Analysis and Retrieval System Online (Medline, via Ovid), Embase; Cochrane, and Cumulative Index of Nursing and Allied Health Literature — CINAHL (via EBSCO) databases up to June 2023. The relevant clinical studies in which cell-based therapies were utilized to manage AD were included. The risk of bias was evaluated using the JBI checklists, based on the study designs.

Results:

Out of 1,014 screened records, a total of five studies with 70 individuals (including 59 patients receiving stem cells and 11 placebo controls) were included. In all these studies, despite the discrepancy in the origin of stem cells, cell density, and transplant site, safety goals were obtained. The intracerebroventricular injection of adipose-derived stromal vascular fraction (ADSVF) and umbilical cord-derived mesenchymal stem cells (UC-MSCs), the intravenous injection of Lomecel-B, and the bilateral hippocampi and right precuneus injection of UC-MSCs are not linked to any significant safety concerns, according to the five included studies. Studies also revealed improvements in biomarkers and clinical outcomes as a secondary outcome. Three studies had no control groups and there are concerns regarding the similarity of the groups in others. Also, there is considerable risk of bias regarding the outcome assessment scales.

Conclusion:

Cell-based therapies are well tolerated by AD patients, which emphasizes the need for further, carefully planned randomized studies to reach evidence-based clinical recommendations in this respect.

RESUMO

Atualmente, não há terapia modificadora da doença para a doença de Alzheimer (DA), que é a causa mais prevalente de demência.

Objetivo:

Este estudo teve como objetivo estimar a eficácia e segurança dos tratamentos baseados em células na DA.

Métodos:

Observando os métodos do JBI e a declaração PRISMA, uma busca sistemática foi realizada nas bases de dados PubMed, Medical Literature Analysis and Retrieval System Online — Medline (via Ovid), Embase, Cochrane e CINAHL (via EBSCO) até junho de 2023. Foram incluídos os estudos clínicos relevantes nos quais terapias baseadas em células foram utilizadas para gerenciar a DA. O risco de viés foi avaliado utilizando os checklists do JBI, com base nos desenhos dos estudos.

Resultados:

Dos 1.014 registros examinados, foi incluído um total de cinco estudos com 70 indivíduos (incluindo 59 pacientes que receberam células-tronco e 11 controles de placebo). Em todos esses estudos, apesar da discrepância na origem das células-tronco, densidade celular e local de transplante, os objetivos de segurança foram alcançados. A injeção intracerebroventricular de ADSVF e UC-MSCs, a injeção intravenosa de Lomecel-B e a injeção bilateral dos hipocampos e precuneus direito de UC-MSCs não estão relacionadas a quaisquer preocupações significativas de segurança, de acordo com os cinco estudos incluídos. Os estudos também revelaram melhorias nos biomarcadores e resultados clínicos como um desfecho secundário. Três estudos não tinham grupos de controle e há preocupações quanto à semelhança dos grupos em outros. Além disso, há um risco considerável de viés em relação às escalas de avaliação de desfechos.

Conclusão:

As terapias baseadas em células são bem toleradas por pacientes com DA, o que enfatiza a necessidade de mais estudos randomizados cuidadosamente planejados para alcançar recomendações clínicas baseadas em evidências.

Keywords:

Alzheimer Disease
Cell Transplantation
Stem Cell Transplantation
Systematic Review
Palavras-chave:

Doença de Alzheimer
Transplante de Células
Transplante de Células-Tronco
Revisão Sistemática
The Student Research Committee of Tabriz University of Medical Sciences64063 The Student Research Committee of Tabriz University of Medical Sciences supported this work (grant number: 64063).
==== Body
pmcINTRODUCTION

As the sixth leading cause of mortality1, and the third cause in older adults in the United States, Alzheimer’s Disease (AD) is the most common neurodegenerative disease2. Its prevalence in Europe is about 5.05%3. AD is characterized by progressive neurocognitive dysfunction due to the formation of extracellular amyloid plaques in the brain4. Currently, cholinesterase inhibitors and memantine — an antagonist of the N-Methyl-D-Aspartate — are used for boosting memory function in AD patients. some herbal components are also proposed to be effective; however, there is a lack of evidence for judgment in this regard5-8.

In addition to pharmacological interventions, stem cells (SCs), as a treatment approach, have enough potential to stop or even reverse the disease process and reduce the symptoms of AD9. The conventional belief that the adult central nervous system is incapable of neurogenesis has been disproved by the finding of neural SCs (NSCs)10. The theoretical ability of differentiation of SCs into neurons has been widely reported11,12. Also, evidence demonstrates the capability of transplants to become integrated into complex brain functions13. This potential makes AD one of the primary healthcare areas of cell therapy centers14.

SC replacement can cause the formation and maintenance of neural networks in the nervous system and prevent the progression of the disease by supporting the remaining cells and preventing the accumulation and production of toxic factors. Release of neurotrophins such as nerve growth factor (NGF), upregulating the expression of the anti-apoptotic factors, inhibition of activated microglia, as well as alleviating oxidative stress and inflammation are suggested as the possible mechanisms for the efficacy of mesenchymal SCs (MSCs)15,16. A systematic review of animal models of AD found excellent efficacy for MSCs in reducing cognitive deficits, which supports future clinical studies in this field. Based on nine preclinical studies incorporating 225 animals, MSCs-based treatment was associated with improved learning function and ameliorated the cognitive impairment, based on the Morris water maze test, in animal models of AD17.

Due to the lack of an up-to-date and exhaustive systematic review study on the clinical safety and efficacy of cell-based therapies in AD, such a study is necessary to reach a consensus on the scattered findings.

METHODS

This study observed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement18 and Joanna Briggs Institute (JBI)’s methods for conducting systematic reviews19.

Ethics approval

The research protocol was approved by the Ethics Committee of Tabriz University of Medical Sciences (ethics code: IR.TBZMED.VCR.REC.1398.338)

Inclusion and exclusion criteria

Clinical studies in which cell-based therapies were used to manage patients with AD are included. All of the animal or in vitro studies, case reports, review articles, letters to editors, studies without efficacy or safety data, ongoing clinical trials, and withdrawn studies were excluded.

Search strategy and study selection

A systematic search was conducted in June 2023 in PubMed, Medline (via Ovid), Embase; Cochrane, and Cumulative Index of Nursing and Allied Health Literature — CINAHL, via EBSCO) databases (by F-S.G.). Details about the search strategy are presented in Supplementary Material 1 In addition, the reference list of included studies, as well as the review studies, were manually checked for a comprehensive coverage of the published studies. After removing duplicate studies by EndNote 20 reference manager software, two authors screened the records in two title/abstract (S.S-S. and H.F.) and full text (R.M-H. and A.N.) stages, and studies that met the eligibility criteria were selected for inclusion. Disagreements were resolved by another researcher (H.S-P. or L.R.).

Outcomes and data extraction

The desired outcomes were “efficacy of treatment” and “safety of treatment”. For this purpose, the necessary data, including the first author of the article, published year, study design, severity of AD, disease duration, number of participants, male-to-female ratio, age, type of transplanted SCs, cell density, SCs origin, transplantation zone, follow-up period, efficacy assessment scales, the efficacy of treatments, and safety data extracted by two authors (H.F., or H.K.) were collected using a data extraction table and double-checked by two other authors (M-S.H. and A.N.). The risk of bias (RoB) in the included studies was assessed using the JBI Critical appraisal tool20, by two authors (S.S-S and M-S.H.). Any disagreements during the mentioned stages were referred to another author (H.S-P. or L.R.).

RESULTS

Search results and screening

Overall, 1,543 articles were found through the database search. After duplicate removal, 1,014 studies were screened in the title/abstract stage, of which five were considered for further evaluation in the full-text stage, and all of these articles21-25 were included in the present systematic review (Figure 1).

Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram18.

Notes: *The total number across all databases; **No automation tools were used and all of the records were excluded by the researchers.

Characteristics of the studies

A total of five phase I studies with 70 individuals (including 59 patients receiving SCs and 11 placebo controls) were included in the present systematic review. The males constituted the majority of the included patients (37 males and 33 females). The mean age of participants in the included studies was demonstrated to be more than 60 years, with an approximate range of 61.6 to 75.5 years. Most studies (3 of 5) have utilized human umbilical cord-derived MSCs (UC-MSCs) to evaluate the tolerability of cell therapy among AD patients. Two other studies implemented adipose-derived stromal vascular fraction (ADSVF) and allogeneic MSC formulation (Lomecel-B). Eventually, the scales for outcome assessment were evaluated among the included studies, demonstrating somehow divergent scales, with the most prominent ones being Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Seoul-Instrumental Activities of Daily Living (S-IADL), Mini-Mental State Examination (MMSE), Consortium to Establish a Registry for AD (CERAD), Memory Performance Index (MPI), neuropsychiatric inventory (NPI), Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), as well as the cerebrospinal fluid (CSF) and plasma biomarkers, and imaging modalities including magnetic resonance imaging (MRI), positron emission tomography (PET) and computed tomography (CT). The characteristics of the studies are presented in Table 1.

Table 1 The characteristics and summary of the findings of studies on Alzheimer’s disease patients.

 	P: patients	I: Intervention	O: outcome	
Study	Baseline MMSE	N	M:F	Mean age ± SD	Types of SCT	Cell density	Where cells derived	Transplantation zone	Intervention-outcome measurement interval	Outcome assessment scales	Summary of results	Cognitive outcomes	
Kim et al.24	16.6±4.1	9	6:3	61.6±6.9	human UC-MSCs	(3, 6)×106 cells	umbilical cord blood	bilateral hippocampi and right precuneus	4, 12 weeks, and 24 months	ADAS-Cog,
S-IADL,
MMSE, PiB-PET, FDG-PET, CSF biomarkers, brain CT and MRI	In the 12-week follow-up, wound pain (100%), headache (44.4%), dizziness (33.3%), delirium (33.3%), nausea (22.2%), and back pain (22.2%) were the most common adverse events, none of which were extended to 24 months. There were no structural abnormalities or immunological reactions.	Changes in ADAS-Cog, in the low-dose group, were 5.3±3.5 (week 12) and 20.0±9.9 (month 24); in the high-dose group, they were 3.5±5.6 (week 12) and 8.6±13.1 (month 24).
Changes in S-IADL, in the low-dose group, were 1.7±4.0 (week 12) and 19.5±6.4 (month 24); in the high-dose group, they were 1.2±5.9 (week 12) and 12.0±6.0 (month 24).
Changes in MMSE, in the low-dose group, were -1.7±0.6 (week 12) and -9.5±0.7 (month 24); in the high-dose group, they were 0.5±2.1 (week 12) and -8.4±5.6 (month 24).	
Duma et al.23	Various	10	6:4	75.5±11.6	ADSVF	3.5–20 cc containing 4.05×105 to 6.2×107 cells/cc	liposuction	Intracerebroventricular (Ommaya reservoir implantation)	2 to 36 months	MPI, RBANS, NeuroQuant® volumetric MRI, CSF biomarkers	There was no complication other than mild headache, or pain at the surgical sites, for less than 24 hours. Over eight months, 30% showed an improvement in CSF markers. Hippocampal volume increased in one of four assessed AD patients after 2 years of follow-up.	Over eight months, 80% of AD patients had stable or improved cognitive function, assessed by MPI.	
Kim et al.22	21.1±3.82	9	3:6	62.7±7.93	human UC-MSCs	(1-3)×107 cells/2 mL [three repeated injections]	umbilical cord blood	Intracerebroventricular (Ommaya reservoir implantation)	4,8, 12, 52, 104 weeks	ADAS-Cog,
S-IADL, MMSE, NPI, CIBIC-Plus, CSF biomarkers, MRI, PiB-PET or florbetaben PET	Fever (100%), headache (77.8%), nausea (55.6%), vomiting (44.4%), myalgia or chills (22.2%), paresthesia on both arms and legs (22.2%) were the most commonly reported adverse events, all of which subsided within 36 hours. There were also three serious adverse events in two participants which required an extended hospitalization.	Changes in ADAS-Cog, in the low-dose group were 0.7±4.0, and in the high-dose group, were 2.3±5.0 (week 12)
Changes in S-IADL, in the low-dose group were 2.0±2.0, and in the high-dose group were 1.5±3.0 (week 12)
Changes in MMSE, in the low-dose group, were 0.0±2.0, and, in the high-dose group were 0.7±1.6 (week 12).
Changes in NPI, in the low-dose group, were 1.3±2.3, and, in the high-dose group, were -1.7±5.8 (week 12).	
Myeong et al. 21	21.6±1.39	6 (+3 placebo)	5:4	63.4±3.64	human UC-MSCs	3×107 cells/2 mL	umbilical cord blood	Intracerebroventricular (Ommaya reservoir implantation)	24 hours	CSF pro-inflammatory cytokine	Injection was associated with increased CSF levels of TNF-α, IL-1β, IL-6, and CRP; however, bacterial culture results were negative.	-	
Brody et al.25	20.45±1.46, 20.60±2.06, 20.70±2.26	25 (+ 8 placebo)	17:16	71.2±8.4	Lomecel-B	(2-10)×107 cells	Bone marrow	single intravenous infusion	13, 26, 52 weeks	MMSE, ADAS-Cog-11, ADCS-ADL, ADRQL, GDS, NPI, QOL-AD, Trail Making Test, plasma biomarkers, MRI	There was only one treatment-emergent serious adverse event. The incidence of adverse events was lower in each Lomecel-B treatment arm. There were no amyloid-related imaging abnormalities.	Low-dose (but not high-dose) Lomecel-B arm was significantly better than the placebo at week 13 by 2.69±1.39 points in MMSE. Lomecel-B arms appeared more stable in ADAS-Cog-11, and the difference at week 26 between placebo and low-dose Lomecel-B arms, while not significant, was 5.68±3.66.	
Abbreviations: N, number of patients; M:F, Male:Female; MMSE, Mini-Mental State Examination; AD, Alzheimer’s disease; ADAS-Cog, Alzheimer’s Disease Assessment Scale-Cognitive Subscale; S-IADL, Seoul-Instrumental Activities of Daily Living; CERAD, Consortium to Establish a Registry for Alzheimer’s Disease; MPI, Memory Performance Index; CSF, cerebrospinal fluid; UC-MSCs, umbilical cord blood-derived mesenchymal stem cells; ADSVF, adipose-derived stromal vascular fraction; RBANS, repeatable battery for the assessment of neuropsychological status; MSC, mesenchymal stem cells; NPI, neuropsychiatric inventory; ADCS-ADL, Alzheimer’s Disease Cooperative Study-Activities of Daily Living; ADRQL, Alzheimer’s Disease Cooperative Study-Activities of Daily Living; GDS, Geriatric Depression Scale; QOL-AD, Quality of Life in Alzheimer’s Disease; CIBIC-Plus, Clinician’s Interview-Based Impression of Change Plus Caregiver Input.

Risk of bias assessments

Table 2 presents the details of RoB assessments based on the JBI critical appraisal tool. Three studies had no control groups and the other two studies did not report enough data to judge the similarity of the groups. Also, there is considerable RoB regarding the outcome assessment scales.

Table 2 Details of the risk of bias assessments based on the Joanna Briggs Institute Critical Appraisal tool for Quasi-experimental studies included in this systematic review.

Questions	Author (year)	
Myeong et al.21	Brody et al.25	Kim et al.22	Duna et al.23	Kim et al.24	
Q1: Is it clear in the study what the ‘cause’ is and what the ‘effect’ is (i.e. is there no confusion about which variable comes first)?	Y	Y	Y	Y	Y	
Q2: Were the participants included in any similar comparisons?	U	U	N	U	N	
Q3: Were the participants included in any comparisons receiving similar treatment/care, other than the exposure or intervention of interest?	U	U	N	N	N	
Q4: Was there a control group?	Y	Y	N	N	N	
Q5: Was the data analysis conducted with sufficient coverage of the identified sample?	Y	Y	Y	U	Y	
Q6: Was follow-up complete? And, if not, were differences between groups in terms of their follow-up adequately described and analyzed?	N	Y	Y	N	Y	
Q7: Were the outcomes of participants included in any comparisons measured in the same way?	Y	Y	Y	Y	Y	
Q8: Were outcomes measured in a reliable way?	U	Y	U	U	U	
Q9: Was appropriate statistical analysis used?	Y	U	N	U	N	
Abbreviations: Y, Yes; N, No; U, Unclear.

Results of individual studies

In a phase 1 clinical trial, nine individuals with mild-to-moderate AD (MMSE: 16.6±4.1) produced acceptable and secure outcomes. In this study, in addition to AChE-I, low (3.0*106 cells/60 mL) and high (6.0*106 cells/60 mL) doses of UC-MSCs were injected into the bilateral hippocampi and right precuneus and, during the 12-week follow-up period, there was no considerable safety issues and dose-limiting toxicity. There was no fever or cerebral hemorrhage in control CT scans. Surgical wound pain, headache, dizziness, delirium, nausea, and back pain were the adverse events and in the extended 24-month follow-up there was no adverse event. There were no tumor and subdural hemorrhages in 12-month and 24-month control MRIs. Regarding clinical outcomes, improved ADAS-Cog, S-IADL, and MMSE scores were evident24.

Four years later, Duma et al., in a 3-year phase 1 study, approved the safety of ADSVF injection (3.5–20 cc [median: 4 cc] containing 4.05×105 to 6.2×107 cells/cc) into the human brain ventricular system, receiving through an implanted reservoir or via ventriculoperitoneal shunts. The sample of this study includes ten AD patients with no other treatment options, and reported complications include acute hydrocephalus and severe meningismus after first injection. A decrease in tau protein and an increase in hippocampal volume were reported in two patients with eight injections, and an improved memory index was reported in 30% of the samples23.

Kim et al. performed another phase 1 clinical trial to assess the safety of three repeated intracerebroventricular injections of low (1.0*107 cells/2 mL) and high (3.0*107 cells/2 mL) doses of UC-MSCs on nine mild-to-moderate AD patients in 2021. Injections in this study were associated with three serious adverse events; however, there was no dose-limiting toxicity. Increased CSF levels of white blood cells (WBCs), fever, headache, nausea, and vomiting which all subsided within 36 hours were the most commonly reported adverse events in this study, and serious adverse events were limited to extended hospitalization by one day. There was no tumor development, hydrocephalus, or hemorrhage in the extended observation study for 36 months22. To delineate the cause of fever, researchers conducted another study and assessed the CSF level of multiple cytokines. Investigators demonstrated that transplantation of UC-MSCs was associated with increased levels of inflammation cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and c-reactive protein (CRP) levels, with no bacterial source; therefore, it was concluded that the transient inflammatory response was due to the transplanted UC-MSCs21.

The most recent study was done by Brody et al. in 2023 and involved 33 mild AD patients. Eight patients received a placebo in this double-blind randomized controlled trials (RCT), and 25 underwent a single infusion of low (2.0*107 cells) or high (1.0*108 cells) doses of Lomecel-B, MSCs isolated from fresh bone marrow tissue. In this study, the primary safety endpoint was met, and significant improvement was achieved regarding the neurocognitive, imaging, and CSF biomarkers. In this study, treatment-emergent serious adverse events were observed in one patient in the high-dose group. The overall incidence of adverse events was lower in Lomecel-B groups in comparison to the placebo group and there were no amyloid-related imaging abnormalities25.

Results of synthesis

The evidence regarding cell-based therapies in AD is mostly limited to safety assessments. Based on five included studies, bilateral hippocampi and right precuneus injection of UC-MSCs, intracerebroventricular injection of ADSVF and UC-MSCs, and intravenous injection of Lomecel-B are not associated with considerable safety issues. In addition, as a secondary outcome, studies suggested clinical and biomarker improvements, too.

DISCUSSION

This systematic review was conducted to explore the evidence regarding the efficacy and safety of cell-based therapies in AD patients. Based on the limited available evidence, this procedure seems to be safe and well-tolerated by AD patients in different stages of the disease, and it can be associated with clinical improvements; however, these findings arose from phase 1 clinical trials with small sample size and there is a need for future well-designed RCTs for clinical recommendations in this regard.

The basis of neurodegenerative diseases’ pathogenesis is a progressive loss of function, structure, or number of neurons26. However, the complexity of associated underlying mechanisms prevents understanding the exact pathogenic processes in each disease. Also, the blood-brain barrier causes significant limitations in developing effective pharmacologic agents27. In this condition, regenerating neural tissue, providing neurotrophic support, alleviating neurodegeneration, and stabilizing the neuronal networks by SCs offer promising treatments for almost all neurodegenerative diseases28. SCs can help scientists in the treatment and better understanding of AD-related dementia mechanisms29.

SC therapy, commonly known as regenerative medicine, promotes the repair response of injured tissue30. It is routinely used for cancer and blood-related diseases31. SCs are unspecialized human body cells with the capacity for self-renewal, and can develop into different types of organism cells32. The pluripotency in SCs is a continuum that includes the spectrum from embryonic SCs to multi-, oligo- or unipotent cells33. MSCs, such as adipose-derived MSCs and bone marrow MSCs, are multipotent progenitor cells that can be isolated from multiple human tissues34 and used as a significant source of cells with regenerative and anti-inflammation potential35,36. SVF is also the initial product of adipose tissue37, excluding mature adipocytes38, which include heterogeneous cell populations, among them adipose-derived MSCs, endothelial cells, and macrophages39. NSCs are also the SCs of the nervous system, which can differentiate into neurons, astrocytes, and oligodendrocytes, three major cell types in the central nervous system40.

There is still a slight improvement in cell-based treatments for AD. Although the exact underlying mechanism of how SCs can boost the cognitive function of AD patients is still unclear41, recent studies have found neurogenesis and synaptogenesis as well as reducing Aβ accumulation potential of MCSs42-44. In addition, evidence supports the capability of different SCs to differentiate into cholinergic neurons45. Based on our findings, cell-based treatments were well-tolerated in AD patients, but confirming significant improvements in patients’ conditions needs more well-designed trials with larger sample sizes. Ongoing clinical trials may confirm or reject the current opinions. AstroStem is one of the ongoing trials in the phase 1/2 study. In this trial, the SCs extracted from the fatty tissue of patients and outcome measurement will be based on adverse events and cognitive function, behavior and mood, daily activity, and biomarkers46.

To the best of our knowledge, this study was the first systematic review to assess the efficacy and safety of cell-based therapies in AD. Comprehensive coverage of eligible studies, as well as PRISMA and JBI-guided methods, were the leading strengths of this study. On the other hand, excluding non-English papers was the limitation during the review process and the small number of included studies, small sample sizes, and lack of well-designed RCTs were the main limitations of the evidence.

In conclusion, cell-based therapies are well tolerated in patients with AD. Also, the treatments’ efficacy in reducing disease progression introduces cell-based therapy as a new therapeutic approach in AD; however, the limitations of the evidence highlight the need for future well-designed RCTs. Also, future studies should aim to find the best type and sources of cells, doses, and route of administration in each condition.

ACKNOWLEDGMENTS

The research protocol was approved and supported by the Student Research Committee, Tabriz University of Medical Sciences (grant number: 64063). Also, the study was registered in the International Prospective Register of Systematic Reviews (PROSPERO ID: CRD42020153802). We would like to thank the Clinical Research Development Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran, for their assistance in this research.

Funding: The Student Research Committee of Tabriz University of Medical Sciences supported this work (grant number: 64063).
==== Refs
REFERENCES

1. 1. Taylor CA, Greenlund SF, McGuire LC, Lu H, Croft JB. Deaths from Alzheimer’s Disease – United States, 1999–2014. MMWR Morb Mortal Wkly Rep. 2017;66(20):521-6. https://doi.org/10.15585/mmwr.mm6620a1
Taylor CA Greenlund SF McGuire LC Lu H Croft JB Deaths from Alzheimer’s Disease – United States, 1999–2014 MMWR Morb Mortal Wkly Rep 2017 66 20 521 6 10.15585/mmwr.mm6620a1 28542120
2. 2. James BD, Leurgans SE, Hebert LE, Scherr PA, Yaffe K, Bennett DA. Contribution of Alzheimer disease to mortality in the United States. Neurology. 2014;82(12):1045-50. https://doi.org/10.1212/WNL.0000000000000240
James BD Leurgans SE Hebert LE Scherr PA Yaffe K Bennett DA Contribution of Alzheimer disease to mortality in the United States Neurology 2014 82 12 1045 50 10.1212/WNL.0000000000000240 24598707
3. 3. Niu H, Álvarez-Álvarez I, Guillén-Grima F, Aguinaga-Ontoso I. Prevalence and incidence of Alzheimer’s disease in Europe: a meta-analysis. Neurologia. 2017;32(8):523-32. https://doi.org/10.1016/j.nrl.2016.02.016
Niu H Álvarez-Álvarez I Guillén-Grima F Aguinaga-Ontoso I Prevalence and incidence of Alzheimer’s disease in Europe: a meta-analysis Neurologia 2017 32 8 523 32 10.1016/j.nrl.2016.02.016 27130306
4. 4. Tiwari S, Atluri V, Kaushik A, Yndart A, Nair M. Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics. Int J Nanomedicine. 2019;14:5541-54. https://doi.org/10.2147/IJN.S200490
Tiwari S Atluri V Kaushik A Yndart A Nair M Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics Int J Nanomedicine 2019 14 5541 54 10.2147/IJN.S200490 31410002
5. 5. Majidazar R, Rezazadeh-Gavgani E, Sadigh-Eteghad S, Naseri A. Pharmacotherapy of Alzheimer’s disease: an overview of systematic reviews. Eur J Clin Pharmacol. 2022;78(10):1567-87. https://doi.org/10.1007/s00228-022-03363-6
Majidazar R Rezazadeh-Gavgani E Sadigh-Eteghad S Naseri A Pharmacotherapy of Alzheimer’s disease: an overview of systematic reviews Eur J Clin Pharmacol 2022 78 10 1567 87 10.1007/s00228-022-03363-6 35881170
6. 6. Rasi Marzabadi L, Fazljou SMB, Araj-Khodaei M, Sadigh-Eteghad S, Naseri A, Talebi M. Saffron reduces some inflammation and oxidative stress markers in donepezil-treated mild-to-moderate Alzheimer’s Disease patients: a randomized double-blind placebo-control trial. J Herb Med. 2022;34:100574. https://doi.org/10.1016/j.hermed.2022.100574
Rasi Marzabadi L Fazljou SMB Araj-Khodaei M Sadigh-Eteghad S Naseri A Talebi M Saffron reduces some inflammation and oxidative stress markers in donepezil-treated mild-to-moderate Alzheimer’s Disease patients: a randomized double-blind placebo-control trial J Herb Med 2022 34 100574 10.1016/j.hermed.2022.100574
7. 7. Vo TS, Vo TTBC, Vo TTTN. Characterization and heath effects of saffron utilizing in disease treatment and prevention: a review. J Res Clin Med. 2021;9(1):28. https://doi.org/10.34172/jrcm.2021.028
Vo TS Vo TTBC Vo TTTN Characterization and heath effects of saffron utilizing in disease treatment and prevention: a review J Res Clin Med 2021 9 1 28 10.34172/jrcm.2021.028
8. 8. Gorji N, Moeini R, Memariani Z. Chapter 6 – Herbs for Alzheimer’s disease management – preclinical studies: a narrative. In: Martin CR, Patel VB, Preedy VR, editors. Treatments, nutraceuticals, supplements, and herbal medicine in neurological disorders. Philadelphia: Academic Press; 2023. p. 95-123. https://doi.org/10.1016/B978-0-323-90052-2.00023-8
Gorji N Moeini R Memariani Z Chapter 6 – Herbs for Alzheimer’s disease management – preclinical studies: a narrative. Martin CR Patel VB Preedy VR editors Treatments, nutraceuticals, supplements, and herbal medicine in neurological disorders Philadelphia Academic Press 2023 95 123 10.1016/B978-0-323-90052-2.00023-8
9. 9. Kumar A, Narayanan K, Chaudhary RK, Mishra S, Kumar S, Vinoth KJ, et al. Current perspective of stem cell therapy in neurodegenerative and metabolic diseases. Mol Neurobiol. 2017;54(9):7276-96. https://doi.org/10.1007/s12035-016-0217-4
Kumar A Narayanan K Chaudhary RK Mishra S Kumar S Vinoth KJ Current perspective of stem cell therapy in neurodegenerative and metabolic diseases Mol Neurobiol 2017 54 9 7276 96 10.1007/s12035-016-0217-4 27815831
10. 10. Dantuma E, Merchant S, Sugaya K. Stem cells for the treatment of neurodegenerative diseases. Stem Cell Res Ther. 2010;1(5):37. https://doi.org/10.1186/scrt37
Dantuma E Merchant S Sugaya K Stem cells for the treatment of neurodegenerative diseases Stem Cell Res Ther 2010 1 5 37 10.1186/scrt37 21144012
11. 11. Hernández R, Jiménez-Luna C, Perales-Adán J, Perazzoli G, Melguizo C, Prados J. Differentiation of human mesenchymal stem cells towards neuronal lineage: clinical trials in nervous system disorders. Biomol Ther (Seoul). 2020;28(1):34-44. https://doi.org/10.4062/biomolther.2019.065
Hernández R Jiménez-Luna C Perales-Adán J Perazzoli G Melguizo C Prados J Differentiation of human mesenchymal stem cells towards neuronal lineage: clinical trials in nervous system disorders Biomol Ther (Seoul) 2020 28 1 34 44 10.4062/biomolther.2019.065 31649208
12. 12. George S, Hamblin MR, Abrahamse H. Differentiation of mesenchymal stem cells to neuroglia: in the context of cell signalling. Stem Cell Rev Rep. 2019;15(6):814-26. https://doi.org/10.1007/s12015-019-09917-z
George S Hamblin MR Abrahamse H Differentiation of mesenchymal stem cells to neuroglia: in the context of cell signalling Stem Cell Rev Rep 2019 15 6 814 26 10.1007/s12015-019-09917-z 31515658
13. 13. Blüml S, Kopyov O, Jacques S, Ross BD. Activation of neurotransplants in humans. Exp Neurol. 1999;158(1):121-5. https://doi.org/10.1006/exnr.1999.7073
Blüml S Kopyov O Jacques S Ross BD Activation of neurotransplants in humans Exp Neurol 1999 158 1 121 5 10.1006/exnr.1999.7073 10448423
14. 14. Sánchez-Guijo F, García-Olmo D, Prósper F, Martínez S, Zapata A, Fernández-Avilés F, et al. Spanish Cell Therapy Network (TerCel): 15 years of successful collaborative translational research. Cytotherapy. 2020;22(1):1-5. https://doi.org/10.1016/j.jcyt.2019.11.001
Sánchez-Guijo F García-Olmo D Prósper F Martínez S Zapata A Fernández-Avilés F Spanish Cell Therapy Network (TerCel): 15 years of successful collaborative translational research Cytotherapy 2020 22 1 1 5 10.1016/j.jcyt.2019.11.001 31866320
15. 15. Ghasemi M, Roshandel E, Mohammadian M, Farhadihosseinabadi B, Akbarzadehlaleh P, Shamsasenjan K. Mesenchymal stromal cell-derived secretome-based therapy for neurodegenerative diseases: overview of clinical trials. Stem Cell Res Ther. 2023;14(1):122. https://doi.org/10.1186/s13287-023-03264-0
Ghasemi M Roshandel E Mohammadian M Farhadihosseinabadi B Akbarzadehlaleh P Shamsasenjan K Mesenchymal stromal cell-derived secretome-based therapy for neurodegenerative diseases: overview of clinical trials Stem Cell Res Ther 2023 14 1 122 10.1186/s13287-023-03264-0 37143147
16. 16. Maldonado VV, Patel NH, Smith EE, Barnes CL, Gustafson MP, Rao RR, et al. Clinical utility of mesenchymal stem/stromal cells in regenerative medicine and cellular therapy. J Biol Eng. 2023;17(1):44. https://doi.org/10.1186/s13036-023-00361-9
Maldonado VV Patel NH Smith EE Barnes CL Gustafson MP Rao RR Clinical utility of mesenchymal stem/stromal cells in regenerative medicine and cellular therapy J Biol Eng 2023 17 1 44 10.1186/s13036-023-00361-9 37434264
17. 17. Ge M, Zhang Y, Hao Q, Zhao Y, Dong B. Effects of mesenchymal stem cells transplantation on cognitive deficits in animal models of Alzheimer’s disease: a systematic review and meta-analysis. Brain Behav. 2018;8(7):e00982. https://doi.org/10.1002/brb3.982
Ge M Zhang Y Hao Q Zhao Y Dong B Effects of mesenchymal stem cells transplantation on cognitive deficits in animal models of Alzheimer’s disease: a systematic review and meta-analysis Brain Behav 2018 8 7 e00982 10.1002/brb3.982 29877067
18. 18. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. https://doi.org/10.1136/bmj.n71
Page MJ McKenzie JE Bossuyt PM Boutron I Hoffmann TC Mulrow CD The PRISMA 2020 statement: an updated guideline for reporting systematic reviews BMJ 2021 372 n71 10.1136/bmj.n71 33782057
19. 19. Aromataris E, Lockwood C, Porritt K, Pilla B, Jordan Z, editors. JBI Manual for Evidence Synthesis [Internet]. JBI; 2024 [cited on Oct. 08, 2021]. Available from: https://jbi-global-wiki.refined.site/space/MANUAL
Aromataris E Lockwood C Porritt K Pilla B Jordan Z editors JBI Manual for Evidence Synthesis [Internet] JBI 2024 [cited on Oct. 08, 2021] Available from: https://jbi-global-wiki.refined.site/space/MANUAL
20. 20. Tufanaru C, Munn Z, Aromataris EC, Campbell J, Hopp L. Chapter 3: Systematic reviews of effectiveness. In: Aromataris E, Lockwood C, Porritt K, Pilla B, Jordan Z, editors. JBI Manual for Evidence Synthesis. JBI; 2024. https://doi.org/10.46658/JBIRM-17-03
Tufanaru C Munn Z Aromataris EC Campbell J Hopp L Chapter 3: Systematic reviews of effectiveness. In: Aromataris E Lockwood C Porritt K Pilla B Jordan Z editors JBI Manual for Evidence Synthesis JBI 2024 10.46658/JBIRM-17-03
21. 21. Myeong SH, Kim H, Lee NK, Hwang JW, Kim HJ, Jang H, et al. Intracerebroventricular administration of human umbilical cord blood-derived mesenchymal stem cells induces transient inflammation in a transgenic mouse model and patients with Alzheimer’s disease. Biomedicines. 2022;10(3):563. https://doi.org/10.3390/biomedicines10030563
Myeong SH Kim H Lee NK Hwang JW Kim HJ Jang H Intracerebroventricular administration of human umbilical cord blood-derived mesenchymal stem cells induces transient inflammation in a transgenic mouse model and patients with Alzheimer’s disease Biomedicines 2022 10 3 563 10.3390/biomedicines10030563 35327365
22. 22. Kim HJ, Cho KR, Jang H, Lee NK, Jung YH, Kim JP, et al. Intracerebroventricular injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: a phase I clinical trial. Alzheimers Res Ther. 2021;13(1):154. https://doi.org/10.1186/s13195-021-00897-2
Kim HJ Cho KR Jang H Lee NK Jung YH Kim JP Intracerebroventricular injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: a phase I clinical trial Alzheimers Res Ther 2021 13 1 154 10.1186/s13195-021-00897-2 34521461
23. 23. Duma C, Kopyov O, Kopyov A, Berman M, Lander E, Berman S, et al. Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction for neurodegenerative disorders: a 3-year phase 1 study of 113 injections in 31 patients. Stereotact Funct Neurosurg. 2019;97(suppl 1):111.
Duma C Kopyov O Kopyov A Berman M Lander E Berman S Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction for neurodegenerative disorders: a 3-year phase 1 study of 113 injections in 31 patients Stereotact Funct Neurosurg 2019 97 (suppl 1) 111
24. 24. Kim HJ, Seo SW, Chang JW, Lee JI, Kim CH, Chin J, et al. Stereotactic brain injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: a phase 1 clinical trial. Alzheimers Dement (N Y). 2015;1(2):95-102. https://doi.org/10.1016/j.trci.2015.06.007
Kim HJ Seo SW Chang JW Lee JI Kim CH Chin J Stereotactic brain injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: a phase 1 clinical trial Alzheimers Dement (N Y) 2015 1 2 95 102 10.1016/j.trci.2015.06.007 29854930
25. 25. Brody M, Agronin M, Herskowitz BJ, Bookheimer SY, Small GW, Hitchinson B, et al. Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer’s disease. Alzheimers Dement. 2023;19(1):261-73. https://doi.org/10.1002/alz.12651
Brody M Agronin M Herskowitz BJ Bookheimer SY Small GW Hitchinson B Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer’s disease Alzheimers Dement 2023 19 1 261 73 10.1002/alz.12651 35357079
26. 26. Hung CW, Chen YC, Hsieh WL, Chiou SH, Kao CL. Ageing and neurodegenerative diseases. Ageing Res Rev. 2010;9 Suppl 1:S36-46. https://doi.org/10.1016/j.arr.2010.08.006
Hung CW Chen YC Hsieh WL Chiou SH Kao CL Ageing and neurodegenerative diseases Ageing Res Rev 2010 9 Suppl 1 S36 46 10.1016/j.arr.2010.08.006 20732460
27. 27. Helms HC, Abbott NJ, Burek M, Cecchelli R, Couraud PO, Deli MA, et al. In vitro models of the blood-brain barrier: an overview of commonly used brain endothelial cell culture models and guidelines for their use. J Cereb Blood Flow Metab. 2016;36(5):862-90. https://doi.org/10.1177/0271678X16630991
Helms HC Abbott NJ Burek M Cecchelli R Couraud PO Deli MA In vitro models of the blood-brain barrier: an overview of commonly used brain endothelial cell culture models and guidelines for their use J Cereb Blood Flow Metab 2016 36 5 862 90 10.1177/0271678X16630991 26868179
28. 28. Sakthiswary R, Raymond AA. Stem cell therapy in neurodegenerative diseases: from principles to practice. Neural Regen Res. 2012;7(23):1822-31. https://doi.org/10.3969/j.issn.1673-5374.2012.23.009
Sakthiswary R Raymond AA Stem cell therapy in neurodegenerative diseases: from principles to practice Neural Regen Res 2012 7 23 1822 31 10.3969/j.issn.1673-5374.2012.23.009 25624807
29. 29. Chakari-Khiavi F, Dolati S, Chakari-Khiavi A, Abbaszadeh H, Aghebati-Maleki L, Pourlak T, et al. Prospects for the application of mesenchymal stem cells in Alzheimer’s disease treatment. Life Sci. 2019;231:116564. https://doi.org/10.1016/j.lfs.2019.116564
Chakari-Khiavi F Dolati S Chakari-Khiavi A Abbaszadeh H Aghebati-Maleki L Pourlak T Prospects for the application of mesenchymal stem cells in Alzheimer’s disease treatment Life Sci 2019 231 116564 10.1016/j.lfs.2019.116564 31202840
30. 30. Galindo LT, Filippo TR, Semedo P, Ariza CB, Moreira CM, Camara NOS, et al. Mesenchymal stem cell therapy modulates the inflammatory response in experimental traumatic brain injury. Neurol Res Int. 2011;2011:564089. https://doi.org/10.1155/2011/564089
Galindo LT Filippo TR Semedo P Ariza CB Moreira CM Camara NOS Mesenchymal stem cell therapy modulates the inflammatory response in experimental traumatic brain injury Neurol Res Int 2011 2011 564089 10.1155/2011/564089 21766025
31. 31. Baird SM. Hematopoietic stem cells in leukemia and lymphoma. In: Sell S. Stem cells handbook. Totowa: Springer; 2004. p. 163-75. https://doi.org/10.1007/978-1-59259-411-5_15
Baird SM Hematopoietic stem cells in leukemia and lymphoma. Sell S Stem cells handbook Totowa Springer 2004 163 75 10.1007/978-1-59259-411-5_15
32. 32. Worku MG. Pluripotent and multipotent stem cells and current therapeutic applications: review. Stem Cells Cloning. 2021;14:3-7. https://doi.org/10.2147/SCCAA.S304887
Worku MG Pluripotent and multipotent stem cells and current therapeutic applications: review Stem Cells Cloning 2021 14 3 7 10.2147/SCCAA.S304887 33880040
33. 33. Zakrzewski W, Dobrzyński M, Szymonowicz M, Rybak Z. Stem cells: past, present, and future. Stem Cell Res Ther. 2019;10(1):68. https://doi.org/10.1186/s13287-019-1165-5
Zakrzewski W Dobrzyński M Szymonowicz M Rybak Z Stem cells: past, present, and future Stem Cell Res Ther 2019 10 1 68 10.1186/s13287-019-1165-5 30808416
34. 34. Jin W, He Y, Li T, Long F, Qin X, Yuan Y, et al. Rapid and robust derivation of mesenchymal stem cells from human pluripotent stem cells via temporal induction of neuralized ectoderm. Cell Biosci. 2022;12(1):31. https://doi.org/10.1186/s13578-022-00753-2
Jin W He Y Li T Long F Qin X Yuan Y Rapid and robust derivation of mesenchymal stem cells from human pluripotent stem cells via temporal induction of neuralized ectoderm Cell Biosci 2022 12 1 31 10.1186/s13578-022-00753-2 35292115
35. 35. Bora P, Majumdar AS. Adipose tissue-derived stromal vascular fraction in regenerative medicine: a brief review on biology and translation. Stem Cell Res Ther. 2017;8(1):145. https://doi.org/10.1186/s13287-017-0598-y
Bora P Majumdar AS Adipose tissue-derived stromal vascular fraction in regenerative medicine: a brief review on biology and translation Stem Cell Res Ther 2017 8 1 145 10.1186/s13287-017-0598-y 28619097
36. 36. Davand-Barenji B, Eskandani M, Rahbarghazi R, Geranmayeh MH. Mesenchymal stem cell secretome induced the acquisition of anti-inflammatory phenotype in rat cortical microglia in vitro. J Res Clin Med. 2022;10(1):22. https://doi.org/10.34172/jrcm.2022.022
Davand-Barenji B Eskandani M Rahbarghazi R Geranmayeh MH Mesenchymal stem cell secretome induced the acquisition of anti-inflammatory phenotype in rat cortical microglia in vitro J Res Clin Med 2022 10 1 22 10.34172/jrcm.2022.022
37. 37. Quimby JM. Chronic kidney disease: stem cell therapy. In: Little SE, editor. August’s consultations in feline internal medicine. St. Louis: W.B. Saunders; 2016. p. 477-82.
Quimby JM Chronic kidney disease: stem cell therapy. Little SE editor August’s consultations in feline internal medicine St. Louis W.B. Saunders 2016 477 82
38. 38. Brown AC. Insights into the adipose stem cell niche in health and disease. In: Kokai L, Marra K, Rubin JP, editors. Scientific principles of adipose stem cells. Cambridge: Academic Press; 2022. p. 57-80.
Brown AC Insights into the adipose stem cell niche in health and disease. Kokai L Marra K Rubin JP editors Scientific principles of adipose stem cells Cambridge Academic Press 2022 57 80
39. 39. Han S, Sun HM, Hwang KC, Kim SW. Adipose-derived stromal vascular fraction cells: update on clinical utility and efficacy. Crit Rev Eukaryot Gene Expr. 2015;25(2):145-52. https://doi.org/10.1615/critreveukaryotgeneexpr.2015013057
Han S Sun HM Hwang KC Kim SW Adipose-derived stromal vascular fraction cells: update on clinical utility and efficacy Crit Rev Eukaryot Gene Expr 2015 25 2 145 52 10.1615/critreveukaryotgeneexpr.2015013057 26080608
40. 40. Zhao X, Moore DL. Neural stem cells: developmental mechanisms and disease modeling. Cell Tissue Res. 2018;371(1):1-6. https://doi.org/10.1007/s00441-017-2738-1
Zhao X Moore DL Neural stem cells: developmental mechanisms and disease modeling Cell Tissue Res 2018 371 1 1 6 10.1007/s00441-017-2738-1 29196810
41. 41. Guo Z, Zhang L, Wu Z, Chen Y, Wang F, Chen G. In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model. Cell Stem Cell. 2014;14(2):188-202. https://doi.org/10.1016/j.stem.2013.12.001
Guo Z Zhang L Wu Z Chen Y Wang F Chen G In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer’s disease model Cell Stem Cell 2014 14 2 188 202 10.1016/j.stem.2013.12.001 24360883
42. 42. Moreno-Jiménez EP, Flor-García M, Terreros-Roncal J, Rábano A, Cafini F, Pallas-Bazarra N, et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nat Med. 2019;25(4):554-60. https://doi.org/10.1038/s41591-019-0375-9
Moreno-Jiménez EP Flor-García M Terreros-Roncal J Rábano A Cafini F Pallas-Bazarra N Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease Nat Med 2019 25 4 554 60 10.1038/s41591-019-0375-9 30911133
43. 43. Oh SH, Kim HN, Park HJ, Shin JY, Lee PH. Mesenchymal stem cells increase hippocampal neurogenesis and neuronal differentiation by enhancing the Wnt signaling pathway in an Alzheimer’s disease model. Cell Transplant. 2015;24(6):1097-109. https://doi.org/10.3727/096368914X679237
Oh SH Kim HN Park HJ Shin JY Lee PH Mesenchymal stem cells increase hippocampal neurogenesis and neuronal differentiation by enhancing the Wnt signaling pathway in an Alzheimer’s disease model Cell Transplant 2015 24 6 1097 109 10.3727/096368914X679237 24612635
44. 44. Sivandzade F, Cucullo L. Regenerative stem cell therapy for neurodegenerative diseases: an overview. Int J Mol Sci. 2021;22(4):2153. https://doi.org/10.3390/ijms22042153
Sivandzade F Cucullo L Regenerative stem cell therapy for neurodegenerative diseases: an overview Int J Mol Sci 2021 22 4 2153 10.3390/ijms22042153 33671500
45. 45. Duan L, Bhattacharyya BJ, Belmadani A, Pan L, Miller RJ, Kessler JA. Stem cell derived basal forebrain cholinergic neurons from Alzheimer’s disease patients are more susceptible to cell death. Mol Neurodegener. 2014;9:3. https://doi.org/10.1186/1750-1326-9-3
Duan L Bhattacharyya BJ Belmadani A Pan L Miller RJ Kessler JA Stem cell derived basal forebrain cholinergic neurons from Alzheimer’s disease patients are more susceptible to cell death Mol Neurodegener 2014 9 3 10.1186/1750-1326-9-3 24401693
46. 46. National Library of Medicine. ClinicalTrials.gov. A study to evaluate the safety and efficacy of AstroStem in treatment of Alzheimer’s disease [Internet]. 2021 [cited on Oct. 08, 2021]. Available from: https://clinicaltrials.gov/study/NCT03117738
National Library of Medicine ClinicalTrials.gov A study to evaluate the safety and efficacy of AstroStem in treatment of Alzheimer’s disease [Internet] 2021 [cited on Oct. 08, 2021] Available from: https://clinicaltrials.gov/study/NCT03117738
