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Am J Respir Crit Care Med
Am J Respir Crit Care Med
ajrccm
American Journal of Respiratory and Critical Care Medicine
1073-449X
1535-4970
American Thoracic Society

38843143
202405-0961ED
10.1164/rccm.202405-0961ED
Editorials
Unraveling the Complexities of Mesenchymal Stromal Cell-based Therapies: One Size Doesn’t Fit All
Weiss Daniel J. 1 2
1 Department of Medicine
2 Department of Bioengineering
University of Vermont
Burlington, Vermont
6 6 2024
15 9 2024
6 6 2024
210 6 709711
Copyright © 2024 by the American Thoracic Society
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern (dgern@thoracic.org).
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pmcCell-based therapy utilizing mesenchymal stromal cells (MSCs) is an exciting and promising potential approach for lung diseases and critical illnesses. The rationale is based on a robust platform in which MSCs isolated from bone marrow, adipose, placental, and other tissues can, after either systemic or direct airway administration, ameliorate inflammation and injury in a wide range of preclinical disease models in both small and large animals (1, 2). Mechanistically, the MSCs are believed to exert protective and reparative effects through release of a range of paracrine mediators, including, but not limited to, antiinflammatory cytokines, growth factors, and extracellular vesicles (3). Other actions—for example, mitochondrial transfer—may also play a role (4).

This platform has led to a growing number of clinical investigations in a range of lung diseases and critical illnesses including both non–coronavirus disease (non–COVID-19) and COVID-19–associated acute respiratory distress syndrome and bronchopulmonary dysplasia (BPD) (5, 6). Although some trials have demonstrated benefit, not all have done so, and the ongoing challenge is to better devise optimal strategies for MSC use that incorporate a better mechanistic understanding of MSC actions in different diseases. Unresolved issues include source and optimal approaches for ex vivo expansion of the MSCs, dose, and dosing regimen. Of increasingly recognized importance, the patient inflammatory phenotype within any given disease entity also significantly affects MSC actions and, thus, potential therapeutic effects (7). The latter reflects the growing appreciation that the MSCs—by virtue of expressing cell surface damage and pathogen-associated molecular pattern receptors, such as the Toll-like receptors—respond to different inflammatory environments by altering their paracrine profile (8). The inflammatory environment also influences MSC clearance. Systemically administered MSCs lodge in the pulmonary capillary bed, where they are cleared over approximately 1–2 days through efferocytosis, apoptosis, and other host immune mechanisms (8). While lodged, they do not engraft but rather respond to the local inflammatory environment, with the resulting release of different profiles of paracrine mediators (9, 10). Some data also suggest that it is the host response to the MSCs that drives the observed beneficial effects rather than direct effects of the MSCs themselves (11, 12).

Another confounding factor is that MSCs isolated from any given tissue source themselves constitute a heterogenous population of cells with different attributes and potential therapeutic implications. This has confounded efforts to date to determine benchmarks for MSC “potency” for any given application. To this end, in this issue of the Journal, the study by Cyr-Depauw and colleagues (pp. 814–827) conducted at the Ottawa Hospital Research Institute provides important new information that helps to discriminate different populations utilizing as their model MSCs derived from umbilical cord blood samples from 5 healthy term donors (13). This is a leading group investigating potential MSC therapeutic approaches for BPD and other diseases. The underlying rationale was that single-cell transcriptomic profiling would identify different MSC populations with different protective and reparative effects. The investigators accordingly present robust data that discriminate the MSCs into two populations, one of which exhibited progenitor characteristics, enriched in genes with functions related to cell division, cell cycle, cell proliferation, DNA transcription, and chromatin organization. The other identified population was comprised of MSCs with fibroblast-like characteristics marked by high expression of genes related to extracellular matrix organization and collagen metabolism. It is interesting that four of the five donor samples exhibited the progenitor transcriptome, whereas the fifth was more fibroblastic. These observations correlate with some previously published data from other groups (14); however, the important step taken here was to then interrogate the different MSC populations in a preclinical rat model of BPD utilizing hyperoxia exposure. The investigators found that the MSCs with progenitor attributes were more protective than those with fibroblastic characteristics and further identified the differential expression of HLA-ABC between these groups as a discriminant that affected both MSC retention in the lung and protective effects. Differential expression of HLA gene expression and cell surface markers has also been observed in other studies in which human bone marrow–derived MSCs were exposed to clinical BAL samples from patients with acute respiratory distress syndrome versus lavage samples from healthy volunteers (15).

All told, the present study by Cyr-Depauw and colleagues provides further evidence that more mechanistic information is required for best clinical implementation of MSC-based cell therapies. In parallel, better understanding of cell therapy manufacturing to regulate production of MSCs with differing abilities is an area of active investigation. There are some limitations to the study, including that MSCs with progenitor attributes from only one of the four donors was assessed in the BPD model. These observations will need to be expanded in more wide-ranging studies. Nonetheless, the present data are an important advance in bringing MSC-based cell therapies to successful clinical use.

Originally Published in Press as DOI: 10.1164/rccm.202405-0961ED on June 6, 2024

Author disclosures are available with the text of this article at www.atsjournals.org.
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References

1. Ting AE Baker EK Champagne J Desai TJ dos Santos CC Heijink IH et al. Proceedings of the ISCT scientific signature series symposium, “Advances in cell and gene therapies for lung diseases and critical illnesses.” Cytotherapy 2022 24 774 788 35613962
2. Curley GF O’Kane CM McAuley DF Matthay MA Laffey JG Cell-based therapies for acute respiratory distress syndrome: where are we now? Am J Respir Crit Care Med 2024 209 789 797 38324017
3. Galipeau J Sensébé L Mesenchymal stromal cells: clinical challenges and therapeutic opportunities Cell Stem Cell 2018 22 824 833 29859173
4. Islam MN Das SR Emin MT Wei M Sun L Westphalen K et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury Nat Med 2012 18 759 765 22504485
5. Kirkham AM Monaghan M Bailey AJM Shorr R Lalu MM Fergusson DA et al. Mesenchymal stem/stromal cell-based therapies for COVID-19: first iteration of a living systematic review and meta-analysis: MSCs and COVID-19 Cytotherapy 2022 24 639 649 35219584
6. Thébaud B Stem cell therapies for neonatal lung diseases: are we there yet? Semin Perinatol 2023 47 151724 36967368
7. Martin TR Zemans RL Ware LB Schmidt EP Riches DWH Bastarache L et al. New insights into clinical and mechanistic heterogeneity of the acute respiratory distress syndrome: summary of the Aspen Lung Conference 2021 Am J Respir Cell Mol Biol 2022 67 284 308 35679511
8. Waterman RS Tomchuck SL Henkle SL Betancourt AM A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype PLoS One 2010 5 e10088 20436665
9. Kusuma GD Carthew J Lim R Frith JE Effect of the microenvironment on mesenchymal stem cell paracrine signaling: opportunities to engineer the therapeutic effect Stem Cells Dev 2017 26 617 631 28186467
10. Abreu SC Rolandsson Enes S Dearborn J Goodwin M Coffey A Borg ZD et al. Lung inflammatory environments differentially alter mesenchymal stromal cell behavior Am J Physiol Lung Cell Mol Physiol 2019 317 L823 L831 31553626
11. Weiss DJ English K Krasnodembskaya A Isaza-Correa JM Hawthorne IJ Mahon BP The necrobiology of mesenchymal stromal cells affects therapeutic efficacy Front Immunol 2019 10 1228 31214185
12. de Witte SFH Luk F Sierra Parraga JM Gargesha M Merino A Korevaar SS et al. Immunomodulation by therapeutic mesenchymal stromal cells (MSC) is triggered through phagocytosis of MSC by monocytic cells Stem Cells 2018 36 602 615 29341339
13. Cyr-Depauw C Cook DP Mižik I Lesage F Vadivel A Renesme L et al. Single-cell RNA sequencing reveals repair features of human umbilical cord mesenchymal stromal cells Am J Respir Crit Care Med 2024 210 814 827 38564376
14. Wang Q Li J Wang S Deng Q Wang K Dai X et al. Single-cell transcriptome profiling reveals molecular heterogeneity in human umbilical cord tissue and culture-expanded mesenchymal stem cells FEBS J 2021 288 5311 5330 33763993
15. Enes SR Hampton TH Barua J McKenna DH dos Santos CC Amiel E et al. Healthy versus inflamed lung environments differentially affect MSCs Eur Respir J 2021 58 2004149 33795318
