Therapeutic Potential of Mesenchymal Stem Cells and Their Secretome in Ameliorating Renal Fibrosis: A Comprehensive Narrative Review
Keywords:
Mesenchymal Stem Cells, Secretome, Renal fibrosis, Kidney regeneration, Extracellular vesicles
Abstract
Chronic kidney disease (CKD) represents a global health challenge with limited therapeutic options, often progressing to end-stage renal disease requiring dialysis or transplantation. Renal fibrosis, characterized by excessive extracellular matrix deposition and loss of functional nephrons, constitutes the final common pathway for most progressive kidney diseases. Conventional therapies primarily target symptoms rather than underlying pathological mechanisms. Mesenchymal stem cells (MSCs) have emerged as promising candidates for regenerative therapy due to their multipotent differentiation capabilities, immunomodulatory properties, and paracrine effects. Growing evidence suggests that the therapeutic benefits of MSCs are predominantly mediated through their secretome—a complex mixture of soluble factors, extracellular vesicles, and exosomes. This narrative review comprehensively examines the current understanding of MSC-based therapies for renal fibrosis, with particular emphasis on their secretome. We explore the mechanisms of action, preclinical evidence, ongoing clinical trials, and challenges in translating MSC secretome-based therapies to clinical applications. Recent advances in secretome characterization, bioengineering approaches to enhance therapeutic efficacy, and targeted delivery strategies are also discussed. Despite promising results, several hurdles remain, including standardization of preparation protocols, identification of key therapeutic components, and optimization of delivery methods. This review highlights the transformative potential of MSC secretome in renal fibrosis treatment while acknowledging the need for further research to realize its full clinical potential.
References
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Lipphardt M, Song JW, Matsumoto K, et al. (2017). The third path of tubulointerstitial fibrosis: aberrant endothelial secretome. Kidney Int, 92(3), 558-568.
Liu B, Ding F, Hu D, et al. (2020). Human umbilical cord mesenchymal stem cell conditioned medium attenuates renal fibrosis by reducing inflammation and epithelial-to-mesenchymal transition via the TLR4/NF-κB signaling pathway in vivo and in vitro. Stem Cell Res Ther, 9(1), 7.
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Matsui F, Babitz SK, Rhee A, Hile KL, Zhang H, Meldrum KK. (2020). Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production. Am J Physiol Renal Physiol, 313(2), F405-F414.
Meng XM, Nikolic-Paterson DJ, Lan HY. (2016). TGF-β: the master regulator of fibrosis. Nat Rev Nephrol, 12(6), 325-338.
Mias C, Lairez O, Trouche E, et al. (2009). Mesenchymal stem cells promote matrix metalloproteinase secretion by cardiac fibroblasts and reduce cardiac ventricular fibrosis after myocardial infarction. Stem Cells, 27(11), 2734-2743.
Nagaishi K, Mizue Y, Chikenji T, et al. (2016). Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes. Sci Rep, 6, 34842.
Nassar W, El-Ansary M, Sabry D, et al. (2016). Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases. Biomater Res, 20, 21.
Nastase MV, Zeng-Brouwers J, Wygrecka M, Schaefer L. (2018). Targeting renal fibrosis: Mechanisms and drug delivery systems. Adv Drug Deliv Rev, 129, 295-307.
Nogueira A, Pires MJ, Oliveira PA. (2017). Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies. In Vivo, 31(1), 1-22.
Packham DK, Fraser IR, Kerr PG, Segal KR. (2016). Allogeneic Mesenchymal Precursor Cells (MPC) in Diabetic Nephropathy: A Randomized, Placebo-controlled, Dose Escalation Study. EBioMedicine, 12, 263-269.
Phinney DG, Pittenger MF. (2017). Concise Review: MSC-Derived Exosomes for Cell-Free Therapy. Stem Cells, 35(4), 851-858.
Saad A, Dietz AB, Herrmann SMS, et al. (2017). Autologous Mesenchymal Stem Cells Increase Cortical Perfusion in Renovascular Disease. J Am Soc Nephrol, 28(9), 2777-2785.
Saparov A, Ogay V, Nurgozhin T, Jumabay M, Chen WC. (2016). Preconditioning of Human Mesenchymal Stem Cells to Enhance Their Regulation of the Immune Response. Stem Cells Int, 2016, 3924858.
Shen B, Liu J, Zhang F, et al. (2018). CCR2 Positive Exosome Released by Mesenchymal Stem Cells Suppresses Macrophage Functions and Alleviates Ischemia/Reperfusion-Induced Renal Injury. Stem Cells Int, 2018, 5080291.
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Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. (2017). Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int J Mol Sci, 18(9), 1852.
Wang B, Jia H, Zhang B, et al. (2016). Pre-incubation with hucMSC-exosomes prevents cisplatin-induced nephrotoxicity by activating autophagy. Stem Cell Res Ther, 8(1), 75.
Wang Y, Fu B, Sun X, et al. (2020). miR-let-7c-5p modulates microglia polarization via TLR4 pathway in intracerebral hemorrhage. J Neuroinflammation, 16(1), 168.
Webster AC, Nagler EV, Morton RL, Masson P. (2017). Chronic Kidney Disease. Lancet, 389(10075), 1238-1252.
Wu H, Wen Y, Zhou J, et al. (2020). Exosomes from mesenchymal stem cells improve photoreceptor cell survival in retinal detachment by attenuating pyroptosis activation via miR-544/NLRP1 signaling. Exp Eye Res, 200, 108253.
Yuan X, Logan TM, Ma T. (2019). Metabolism in Human Mesenchymal Stromal Cells: A Missing Link Between hMSC Biomanufacturing and Therapy? Front Immunol, 10, 977.
Zhao YG, Zhang L, Yang F, et al. (2019). The antifibrotic drug pirfenidone inhibits tubular epithelial-mesenchymal transition and attenuates renal interstitial fibrosis in CKD. Clin Transl Med, 8(1), 13.
Zhu XY, Urbieta-Caceres V, Krier JD, et al. (2017). Mesenchymal stem cells and endothelial progenitor cells decrease renal injury in experimental swine renal artery stenosis through different mechanisms. Stem Cells, 31(1), 117-125.
Zou X, Zhang G, Cheng Z, et al. (2014). Microvesicles derived from human Wharton's Jelly mesenchymal stromal cells ameliorate renal ischemia-reperfusion injury in rats by suppressing CX3CL1. Stem Cell Res Ther, 5(2), 40.
Ashammakhi N, Wesseling-Perry K, Hasan A, et al. (2018). Kidney-on-a-chip: untapped opportunities. Kidney Int, 94(6), 1073-1086.
Bruno S, Chiabotto G, Favaro E, Deregibus MC, Camussi G. (2019). Role of extracellular vesicles in stem cell biology. Am J Physiol Cell Physiol, 317(2), C303-C313.
Bruno S, Grange C, Deregibus MC, et al. (2015). Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol, 20(5), 1053-1067.
Bruno S, Porta S, Bussolati B. (2016). Extracellular vesicles in renal tissue damage and regeneration. Eur J Pharmacol, 790, 83-91.
Cantaluppi V, Gatti S, Medica D, et al. (2015). Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia-reperfusion injury by microRNA-dependent reprogramming of resident renal cells. Kidney Int, 82(4), 412-427.
Caplan AI, Correa D. (2011). The MSC: an injury drugstore. Cell Stem Cell, 9(1), 11-15.
Chen CY, Rao SS, Ren L, et al. (2019). Exosomal DMBT1 from human urine-derived stem cells facilitates diabetic wound repair by promoting angiogenesis. Theranostics, 8(6), 1607-1623.
Chen L, Wang Y, Li S, et al. (2017). Exosomes derived from GDNF-modified human adipose mesenchymal stem cells ameliorate peritubular capillary loss in tubulointerstitial fibrosis by activating the SIRT1/eNOS signaling pathway. Theranostics, 10(22), 9425-9442.
Choi HY, Moon SJ, Ratliff BB, et al. (2018). Microparticles from kidney-derived mesenchymal stem cells act as carriers of proangiogenic signals and contribute to recovery from acute kidney injury. PLoS One, 9(2), e87853.
Dominici M, Le Blanc K, Mueller I, et al. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8(4), 315-317.
Doorn J, Moll G, Le Blanc K, van Blitterswijk C, de Boer J. (2012). Therapeutic applications of mesenchymal stromal cells: paracrine effects and potential improvements. Tissue Eng Part B Rev, 18(2), 101-115.
Duffield JS. (2014). Cellular and molecular mechanisms in kidney fibrosis. J Clin Invest, 124(6), 2299-2306.
Eirin A, Lerman LO. (2017). Mesenchymal stem cell-derived extracellular vesicles for renal repair. Curr Gene Ther, 17(1), 29-34.
Eirin A, Zhu XY, Puranik AS, et al. (2017). Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation. Kidney Int, 92(1), 114-124.
Ferreira JR, Teixeira GQ, Santos SG, Barbosa MA, Almeida-Porada G, Gonçalves RM. (2018). Mesenchymal Stromal Cell Secretome: Influencing Therapeutic Potential by Cellular Pre-conditioning. Front Immunol, 9, 2837.
GBD Chronic Kidney Disease Collaboration. (2020). Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet, 395(10225), 709-733.
Geng Y, Zhang L, Fu B, et al. (2014). Mesenchymal stem cells ameliorate rhabdomyolysis-induced acute kidney injury via the activation of M2 macrophages. Stem Cell Res Ther, 5(3), 80.
Gewin LS. (2018). Renal fibrosis: Primacy of the proximal tubule. Matrix Biol, 68-69, 248-262.
Grande MT, Sánchez-Laorden B, López-Blau C, et al. (2015). Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat Med, 21(9), 989-997.
Grange C, Tritta S, Tapparo M, et al. (2019). Stem cell-derived extracellular vesicles inhibit and revert fibrosis progression in a mouse model of diabetic nephropathy. Sci Rep, 9(1), 4468.
He J, Wang Y, Lu X, et al. (2020). Micro-vesicles derived from bone marrow stem cells protect the kidney both in vivo and in vitro by microRNA-dependent repairing. Nephrology (Carlton), 20(9), 591-600.
He J, Wang Y, Sun S, et al. (2016). Bone marrow stem cells-derived microvesicles protect against renal injury in the mouse remnant kidney model. Nephrology (Carlton), 17(5), 493-500.
Humphreys BD. (2018). Mechanisms of Renal Fibrosis. Annu Rev Physiol, 80, 309-326.
Jha JC, Banal C, Chow BS, Cooper ME, Jandeleit-Dahm K. (2016). Diabetes and Kidney Disease: Role of Oxidative Stress. Antioxid Redox Signal, 25(12), 657-684.
Jha V, Garcia-Garcia G, Iseki K, et al. (2013). Chronic kidney disease: global dimension and perspectives. Lancet, 382(9888), 260-272.
Jin J, Shi Y, Gong J, et al. (2019). Exosome secreted from adipose-derived stem cells attenuates diabetic nephropathy by promoting autophagy flux and inhibiting apoptosis in podocyte. Stem Cell Res Ther, 10(1), 95.
Kamerkar S, LeBleu VS, Sugimoto H, et al. (2017). Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature, 546(7659), 498-503.
LeBleu VS, Taduri G, O'Connell J, et al. (2013). Origin and function of myofibroblasts in kidney fibrosis. Nat Med, 19(8), 1047-1053.
Lipphardt M, Song JW, Matsumoto K, et al. (2017). The third path of tubulointerstitial fibrosis: aberrant endothelial secretome. Kidney Int, 92(3), 558-568.
Liu B, Ding F, Hu D, et al. (2020). Human umbilical cord mesenchymal stem cell conditioned medium attenuates renal fibrosis by reducing inflammation and epithelial-to-mesenchymal transition via the TLR4/NF-κB signaling pathway in vivo and in vitro. Stem Cell Res Ther, 9(1), 7.
Martínez-Salgado C, Fuente-Calvo I, García-Cenador B, Santos E, López-Novoa JM. (2021). Involvement of H- and N-Ras isoforms in transforming growth factor-beta1-induced proliferation and in collagen and fibronectin synthesis. Exp Cell Res, 312(11), 2093-2106.
Matsui F, Babitz SK, Rhee A, Hile KL, Zhang H, Meldrum KK. (2020). Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production. Am J Physiol Renal Physiol, 313(2), F405-F414.
Meng XM, Nikolic-Paterson DJ, Lan HY. (2016). TGF-β: the master regulator of fibrosis. Nat Rev Nephrol, 12(6), 325-338.
Mias C, Lairez O, Trouche E, et al. (2009). Mesenchymal stem cells promote matrix metalloproteinase secretion by cardiac fibroblasts and reduce cardiac ventricular fibrosis after myocardial infarction. Stem Cells, 27(11), 2734-2743.
Nagaishi K, Mizue Y, Chikenji T, et al. (2016). Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes. Sci Rep, 6, 34842.
Nassar W, El-Ansary M, Sabry D, et al. (2016). Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases. Biomater Res, 20, 21.
Nastase MV, Zeng-Brouwers J, Wygrecka M, Schaefer L. (2018). Targeting renal fibrosis: Mechanisms and drug delivery systems. Adv Drug Deliv Rev, 129, 295-307.
Nogueira A, Pires MJ, Oliveira PA. (2017). Pathophysiological Mechanisms of Renal Fibrosis: A Review of Animal Models and Therapeutic Strategies. In Vivo, 31(1), 1-22.
Packham DK, Fraser IR, Kerr PG, Segal KR. (2016). Allogeneic Mesenchymal Precursor Cells (MPC) in Diabetic Nephropathy: A Randomized, Placebo-controlled, Dose Escalation Study. EBioMedicine, 12, 263-269.
Phinney DG, Pittenger MF. (2017). Concise Review: MSC-Derived Exosomes for Cell-Free Therapy. Stem Cells, 35(4), 851-858.
Saad A, Dietz AB, Herrmann SMS, et al. (2017). Autologous Mesenchymal Stem Cells Increase Cortical Perfusion in Renovascular Disease. J Am Soc Nephrol, 28(9), 2777-2785.
Saparov A, Ogay V, Nurgozhin T, Jumabay M, Chen WC. (2016). Preconditioning of Human Mesenchymal Stem Cells to Enhance Their Regulation of the Immune Response. Stem Cells Int, 2016, 3924858.
Shen B, Liu J, Zhang F, et al. (2018). CCR2 Positive Exosome Released by Mesenchymal Stem Cells Suppresses Macrophage Functions and Alleviates Ischemia/Reperfusion-Induced Renal Injury. Stem Cells Int, 2018, 5080291.
Tang PM, Nikolic-Paterson DJ, Lan HY. (2019). Macrophages: versatile players in renal inflammation and fibrosis. Nat Rev Nephrol, 15(3), 144-158.
Théry C, Witwer KW, Aikawa E, et al. (2018). Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles, 7(1), 1535750.
Tomasoni S, Longaretti L, Rota C, et al. (2013). Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. Stem Cells Dev, 22(5), 772-780.
Tonelli M, Wiebe N, Knoll G, et al. (2018). Systematic review: kidney transplantation compared with dialysis in clinically relevant outcomes. Am J Transplant, 11(10), 2093-2109.
Tran C, Damaser MS. (2015). Stem cells as drug delivery methods: application of stem cell secretome for regeneration. Adv Drug Deliv Rev, 82-83, 1-11.
Ullah I, Subbarao RB, Rho GJ. (2015). Human mesenchymal stem cells - current trends and future prospective. Biosci Rep, 35(2), e00191.
van Balkom BWM, Eisele AS, Pegtel DM, Bervoets S, Verhaar MC. (2019). Quantitative and qualitative analysis of small RNAs in human endothelial cells and exosomes provides insights into localized RNA processing, degradation and sorting. J Extracell Vesicles, 4, 26760.
van Koppen A, Joles JA, van Balkom BW, et al. (2012). Human embryonic mesenchymal stem cell-derived conditioned medium rescues kidney function in rats with established chronic kidney disease. PLoS One, 7(6), e38746.
Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. (2017). Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int J Mol Sci, 18(9), 1852.
Wang B, Jia H, Zhang B, et al. (2016). Pre-incubation with hucMSC-exosomes prevents cisplatin-induced nephrotoxicity by activating autophagy. Stem Cell Res Ther, 8(1), 75.
Wang Y, Fu B, Sun X, et al. (2020). miR-let-7c-5p modulates microglia polarization via TLR4 pathway in intracerebral hemorrhage. J Neuroinflammation, 16(1), 168.
Webster AC, Nagler EV, Morton RL, Masson P. (2017). Chronic Kidney Disease. Lancet, 389(10075), 1238-1252.
Wu H, Wen Y, Zhou J, et al. (2020). Exosomes from mesenchymal stem cells improve photoreceptor cell survival in retinal detachment by attenuating pyroptosis activation via miR-544/NLRP1 signaling. Exp Eye Res, 200, 108253.
Yuan X, Logan TM, Ma T. (2019). Metabolism in Human Mesenchymal Stromal Cells: A Missing Link Between hMSC Biomanufacturing and Therapy? Front Immunol, 10, 977.
Zhao YG, Zhang L, Yang F, et al. (2019). The antifibrotic drug pirfenidone inhibits tubular epithelial-mesenchymal transition and attenuates renal interstitial fibrosis in CKD. Clin Transl Med, 8(1), 13.
Zhu XY, Urbieta-Caceres V, Krier JD, et al. (2017). Mesenchymal stem cells and endothelial progenitor cells decrease renal injury in experimental swine renal artery stenosis through different mechanisms. Stem Cells, 31(1), 117-125.
Zou X, Zhang G, Cheng Z, et al. (2014). Microvesicles derived from human Wharton's Jelly mesenchymal stromal cells ameliorate renal ischemia-reperfusion injury in rats by suppressing CX3CL1. Stem Cell Res Ther, 5(2), 40.
Published
2025-10-09
How to Cite
Amansyah, F., & Amalina, N. D. (2025). Therapeutic Potential of Mesenchymal Stem Cells and Their Secretome in Ameliorating Renal Fibrosis: A Comprehensive Narrative Review. International Journal of Cell and Biomedical Science, 3(8), 240-253. https://doi.org/10.59278/cbs.v3i8.55
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Review Articles
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