Therapeutic Effects of Mesenchymal Stromal Cells Require Mitochondrial Transfer and Quality Control
Open accessAbstract
Due to their beneficial effects in an array of diseases, Mesenchymal Stromal Cells (MSCs) have been the focus of intense preclinical research and clinical implementation for decades. MSCs have multilineage differentiation capacity, support hematopoiesis, secrete pro-regenerative factors and exert immunoregulatory functions promoting homeostasis and the resolution of injury/inflammation. The main effects of MSCs include modulation of immune cells (macrophages, neutrophils, and lymphocytes), secretion of antimicrobial peptides, and transfer of mitochondria (Mt) to injured cells. These actions can be enhanced by priming (i.e., licensing) MSCs prior to exposure to deleterious microenvironments. Preclinical evidence suggests that MSCs can exert therapeutic effects in a variety of pathological states, including cardiac, respiratory, hepatic, renal, and neurological diseases. One of the key emerging beneficial actions of MSCs is the improvement of mitochondrial functions in the injured tissues by enhancing mitochondrial quality control (MQC). Recent advances in the understanding of cellular MQC, including mitochondrial biogenesis, mitophagy, fission, and fusion, helped uncover how MSCs enhance these processes. Specifically, MSCs have been suggested to regulate peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α)-dependent biogenesis, Parkin-dependent mitophagy, and Mitofusins (Mfn1/2) or Dynamin Related Protein-1 (Drp1)-mediated fission/fusion. In addition, previous studies also verified mitochondrial transfer from MSCs through tunneling nanotubes and via microvesicular transport. Combined, these effects improve mitochondrial functions, thereby contributing to the resolution of injury and inflammation. Thus, uncovering how MSCs affect MQC opens new therapeutic avenues for organ injury, and the transplantation of MSC-derived mitochondria to injured tissues might represent an attractive new therapeutic approach.
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MSCs can engulf and degrade dysfunctional mitochondria released from injured cells.
“MSCs can engulf and degrade dysfunctional Mt released from injured cells [122].”
From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [122]
This process boosts mitochondrial biogenesis within MSCs, enhancing their capacity to donate functional mitochondria to recipient cells, thereby improving overall mitochondrial quality control and metabolic function.
“This process, in turn, boosts mitochondrial biogenesis within the MSCs, enhancing their capacity to donate functional Mt to recipient cells, thereby improving overall mitochondrial quality control (MQC) and metabolic function [122, 123].”
From Mechanisms, efficacy, and future perspectives of cellular-based therapies for liver fibrosis/cirrhosis: focusing on mesenchymal stromal cells (2025) · cites this paper as [122]
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Mesenchymal Stem/Stromal Cells Therapy for Sepsis and Acute Respiratory Distress Syndrome
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Cellules souches mésenchymateuses et médecine régénératrice
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Mesenchymal stem cells alleviate aging in vitro and in vivo
Liu, Q., Song, S., Song, L., Bi, Y., Zhu, K., Qiao, X., Wang, H., Gao, C., Cai, H. N., & Ji, G. (2022) · Annals of Translational Medicine · doi:10.21037/atm-22-1206 · Cited by 23 · see citing works
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Mesenchymal Stem/Stromal Cells in Asthma Therapy: Mechanisms and Strategies for Enhancement
Huang, S., Li, Y., Zeng, J., Chang, N., Cheng, Y., Zhen, X., Zhong, D., Chen, R., Ma, G., & Wang, Y. (2023) · Cell Transplantation · doi:10.1177/09636897231180128 · Cited by 20 · see citing works
Michaeloudes, C., Li, X., Mak, J., & Bhavsar, P. K. (2021) · Methods in molecular biology · doi:10.1007/978-1-0716-1225-5_7 · Cited by 20 · see citing works
Flagged first, then by citations
4 of the 233 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Tissue Engineering and Regenerative Medicine: Perspectives and Challenges
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Integrating Mitochondrial Biology into Innovative Cell Therapies for Neurodegenerative Diseases
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Mitochondria Transfer in Mesenchymal Stem Cells: Unraveling the Mechanism and Therapeutic Potential
Chen, J., Xie, Z., Zhou, H., Ou, Y., Tan, W., Zhang, A., Li, Y., & Fan, X. (2025) · Current Stem Cell Research & Therapy · doi:10.2174/011574888x362739250416153254 · Cited by 10 · see citing works
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Exploring the therapeutic potential of MSC-derived secretomes in neonatal care: focus on BPD and NEC
Azad, T., Wu, F., Mao, J., Zhu, J., Wang, Y., Zhou, X., Hong, K., Xie, H., Qiu, X., Li, B., et al. (2025) · Stem Cell Research & Therapy · doi:10.1186/s13287-025-04616-8 · Cited by 8 · see citing works
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Macrophage niche imprinting as a determinant of macrophage identity and function
Kloc, M., Hałasa, M., & Ghobrial, R. M. (2024) · Cellular Immunology · doi:10.1016/j.cellimm.2024.104825 · Cited by 5 · see citing works
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Targeting mitochondrial dysfunction: Innovative strategies to combat glaucoma neuroinflammation
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Tunneling Nanotube‐Mediated Transcellular Autophagy Alleviates Cadmium Induced Hepatocyte Injury
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Cell-based treatments of lung diseases: overview and outlook
van der Does, A. M., von Schledorn, L., & Olmer, R. (2025) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2025.115712 · Cited by 3 · see citing works
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Hydrogel-based delivery of MSCs and derivatives for improved diabetic retinopathy therapy
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- Authors
- Mukkala, A. N., Jerkic, M., Khan, Z., Szaszi, K., Kapus, A., & Rotstein, O.
- Affiliations
- St. Michael's Hospital (CA)
- Unity Health Toronto, The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, University of Toronto, Toronto, ON M5B 1T8, Canada
- Venue
- International Journal of Molecular Sciences
- Publisher
- MDPI AG
- Published
- 2023-10-31
- Volume
- 24
- Issue
- 21
- Pages
- 15788
- ISSN
- 1422-0067 (ISSN-L)
- PMC
- PMC10647450
- OpenAlex
- W4388048619
- Cited by
- 45
- References
- 233
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 16
- FWCI
- 2.12
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- International Journal of Molecular Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- TSpace (University of Toronto) (submittedVersion, cc-by)
- Funders
- Canadian Institutes of Health Research (CIHR) (#23766, PJT-180624, PJT-178152, AK2023)
- Kidney Foundation of Canada (#23766, PJT-180624, PJT-178152, AK2023)
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- mesenchymal stem cells, mitochondrial transfer, mitochondrial quality control, mitophagy, mitochondrial biogenesis, mitochondrial fission and fusion, PGC-1α, Parkin, mitofusins, Drp1, tunneling nanotubes, extracellular vesicles, organ damage, inflammation resolution, immunomodulation
- MeSH terms
- Humans, Inflammation, Mitochondria, Cell Membrane Structures, Nanotubes, Mesenchymal Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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