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Current Stem Cell Research & Therapy

Editor-in-Chief

ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

Review Article

The Beneficial Effects of Mesenchymal Stem Cells in Acute Kidney Injury: A Narrative Review

Author(s): Yuxiang Liu, Jibin Han, Jingai Fang and Rongshan Li*

Volume 19, Issue 2, 2024

Published on: 16 February, 2023

Page: [200 - 209] Pages: 10

DOI: 10.2174/1574888X18666230206115046

Price: $65

Abstract

Background: Acute kidney injury (AKI) is a multifaced disease characterized by a rapid decline in renal function. However, with growing insight into the pathophysiologic mechanisms of AKI, currently available interventions for AKI are merely supportive. Thus, novel therapies are urgently needed to improve the outcomes of patients with AKI. This narrative review aims to explore enhancing the beneficial effects of Mesenchymal Stem Cells(MSCs) in AKI.

Methods: The authors examined all studies regarding the role of MSCs in AKI. And the authors undertook a structured search of bibliographic databases for peer-reviewed research literature using a focused review question. The most relevant and up-to-date research was included.

Results and Discussion: Based on encouraging preclinical results, stem cell therapy has been widely explored over the last decade. Among the various stem cell types investigated, mesenchymal stem cells are being intensely investigated by virtue of their numerous strengths, such as easy derivation, undemanding cell culture conditions, anti-apoptosis, immunomodulation, and anti-inflammation effects. Mounting evidence suggests that MSCs hold great potential in accelerating kidney repair following AKI in various preclinical models. Unfortunately, low engrafting efficiency and poor survival rate of injected MSCs in the injured renal tissue are major obstacles MSCs clinical application faces.

Conclusion: Various strategies, including genetic manipulation, mimicking the cellular microenvironment with different culture conditions, optimizing MSCs preparation and administration schedule, and screening patients who may more like benefit from MSCs therapy, have been developed to enhance the therapeutic potential of MSCs in AKI.

Graphical Abstract

[1]
Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet 2019; 394(10212): 1949-64.
[http://dx.doi.org/10.1016/S0140-6736(19)32563-2] [PMID: 31777389]
[2]
Liangos O, Wald R, O’Bell JW, Price L, Pereira BJ, Jaber BL. Epidemiology and outcomes of acute renal failure in hospitalized patients: A national survey. Clin J Am Soc Nephrol 2006; 1(1): 43-51.
[http://dx.doi.org/10.2215/CJN.00220605] [PMID: 17699189]
[3]
Hoste EAJ, Bagshaw SM, Bellomo R, et al. Epidemiology of acute kidney injury in critically ill patients: The multinational AKI-EPI study. Intensive Care Med 2015; 41(8): 1411-23.
[http://dx.doi.org/10.1007/s00134-015-3934-7] [PMID: 26162677]
[4]
Forni LG, Darmon M, Ostermann M, et al. Renal recovery after acute kidney injury. Intensive Care Med 2017; 43(6): 855-66.
[http://dx.doi.org/10.1007/s00134-017-4809-x] [PMID: 28466146]
[5]
Hoste EAJ, Kellum JA, Selby NM, et al. Global epidemiology and outcomes of acute kidney injury. Nat Rev Nephrol 2018; 14(10): 607-25.
[http://dx.doi.org/10.1038/s41581-018-0052-0] [PMID: 30135570]
[6]
Lameire NH, Bagga A, Cruz D, et al. Acute kidney injury: An increasing global concern. Lancet 2013; 382(9887): 170-9.
[http://dx.doi.org/10.1016/S0140-6736(13)60647-9] [PMID: 23727171]
[7]
Liu D, Cheng F, Pan S, Liu Z. Stem cells: A potential treatment option for kidney diseases. Stem Cell Res Ther 2020; 11(1): 249.
[http://dx.doi.org/10.1186/s13287-020-01751-2] [PMID: 32586408]
[8]
de Almeida DC, Donizetti-Oliveira C, Barbosa-Costa P, Origassa CS, Câmara NO. In search of mechanisms associated with mesenchymal stem cell-based therapies for acute kidney injury. Clin Biochem Rev 2013; 34(3): 131-44.
[PMID: 24353358]
[9]
Tögel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 2005; 289(1): F31-42.
[http://dx.doi.org/10.1152/ajprenal.00007.2005] [PMID: 15713913]
[10]
Phinney DG, Pittenger MF. Concise Review: MSC-derived exosomes for cell-free therapy. Stem Cells 2017; 35(4): 851-8.
[http://dx.doi.org/10.1002/stem.2575] [PMID: 28294454]
[11]
Aghajani Nargesi A, Lerman LO, Eirin A. Mesenchymal stem cell-derived extracellular vesicles for kidney repair: Current status and looming challenges. Stem Cell Res Ther 2017; 8(1): 273.
[http://dx.doi.org/10.1186/s13287-017-0727-7] [PMID: 29202871]
[12]
Lange C, Tögel F, Ittrich H, et al. Administered mesenchymal stem cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats. Kidney Int 2005; 68(4): 1613-7.
[http://dx.doi.org/10.1111/j.1523-1755.2005.00573.x] [PMID: 16164638]
[13]
Peng X, Xu H, Zhou Y, et al. Human umbilical cord mesenchymal stem cells attenuate cisplatin-induced acute and chronic renal injury. Exp Biol Med 2013; 238(8): 960-70.
[http://dx.doi.org/10.1177/1477153513497176] [PMID: 23970411]
[14]
Luo C, Zhang F, Zhang L, et al. Mesenchymal stem cells ameliorate sepsis-associated acute kidney injury in mice. Shock 2014; 41(2): 123-9.
[http://dx.doi.org/10.1097/SHK.0000000000000080] [PMID: 24169208]
[15]
Tögel FE, Westenfelder C. Kidney protection and regeneration following acute injury: Progress through stem cell therapy. Am J Kidney Dis 2012; 60(6): 1012-22.
[http://dx.doi.org/10.1053/j.ajkd.2012.08.034] [PMID: 23036928]
[16]
Swaminathan M, Stafford-Smith M, Chertow GM, et al. Allogeneic mesenchymal stem cells for treatment of AKI after cardiac surgery. J Am Soc Nephrol 2018; 29(1): 260-7.
[http://dx.doi.org/10.1681/ASN.2016101150] [PMID: 29038286]
[17]
Nitzsche F, Müller C, Lukomska B, Jolkkonen J, Deten A, Boltze J. Concise Review: MSC adhesion cascade—insights into homing and transendothelial migration. Stem Cells 2017; 35(6): 1446-60.
[http://dx.doi.org/10.1002/stem.2614] [PMID: 28316123]
[18]
Karp JM, Leng Teo GS. Mesenchymal stem cell homing: The devil is in the details. Cell Stem Cell 2009; 4(3): 206-16.
[http://dx.doi.org/10.1016/j.stem.2009.02.001] [PMID: 19265660]
[19]
Zhao L, Hu C, Zhang P, Jiang H, Chen J. Novel preconditioning strategies for enhancing the migratory ability of mesenchymal stem cells in acute kidney injury. Stem Cell Res Ther 2018; 9(1): 225.
[http://dx.doi.org/10.1186/s13287-018-0973-3] [PMID: 30139368]
[20]
Ullah M, Liu DD, Thakor AS. Mesenchymal stromal cell homing: Mechanisms and strategies for improvement. iScience 2019; 15: 421-38.
[http://dx.doi.org/10.1016/j.isci.2019.05.004] [PMID: 31121468]
[21]
Liu N, Tian J, Cheng J, Zhang J. Migration of CXCR4 gene-modified bone marrow-derived mesenchymal stem cells to the acute injured kidney. J Cell Biochem 2013; 114(12): 2677-89.
[http://dx.doi.org/10.1002/jcb.24615] [PMID: 23794207]
[22]
Liu N, Patzak A, Zhang J. CXCR4-overexpressing bone marrow-derived mesenchymal stem cells improve repair of acute kidney injury. Am J Physiol Renal Physiol 2013; 305(7): F1064-73.
[http://dx.doi.org/10.1152/ajprenal.00178.2013] [PMID: 23884141]
[23]
Si X, Liu X, Li J, Wu X. Transforming growth factor-β1 promotes homing of bone marrow mesenchymal stem cells in renal ischemia-reperfusion injury. Int J Clin Exp Pathol 2015; 8(10): 12368-78.
[PMID: 26722423]
[24]
Liu N, Wang H, Han G, Tian J, Hu W, Zhang J. Alleviation of apoptosis of bone marrow-derived mesenchymal stem cells in the acute injured kidney by heme oxygenase-1 gene modification. Int J Biochem Cell Biol 2015; 69: 85-94.
[http://dx.doi.org/10.1016/j.biocel.2015.10.007] [PMID: 26456668]
[25]
Liu N, Wang H, Han G, Cheng J, Hu W, Zhang J. Enhanced proliferation and differentiation of HO-1 gene-modified bone marrow-derived mesenchymal stem cells in the acute injured kidney. Int J Mol Med 2018; 42(2): 946-56.
[http://dx.doi.org/10.3892/ijmm.2018.3670] [PMID: 29749549]
[26]
Zhou S, Qiao Y, Liu Y, et al. Bone marrow derived mesenchymal stem cells pretreated with erythropoietin accelerate the repair of acute kidney injury. Cell Biosci 2020; 10(1): 130.
[http://dx.doi.org/10.1186/s13578-020-00492-2] [PMID: 33292452]
[27]
Eliopoulos N, Zhao J, Forner K, Birman E, Young YK, Bouchentouf M. Erythropoietin gene-enhanced marrow mesenchymal stromal cells decrease cisplatin-induced kidney injury and improve survival of allogeneic mice. Mol Ther 2011; 19(11): 2072-83.
[http://dx.doi.org/10.1038/mt.2011.162] [PMID: 21847101]
[28]
Liu N, Han G, Cheng J, Huang J, Tian J. Erythropoietin promotes the repair effect of acute kidney injury by bone-marrow mesenchymal stem cells transplantation. Exp Biol Med (Maywood) 2013; 238(6): 678-86.
[http://dx.doi.org/10.1177/1535370213489486] [PMID: 23918879]
[29]
Hagiwara M, Shen B, Chao L, Chao J. Kallikrein-modified mesenchymal stem cell implantation provides enhanced protection against acute ischemic kidney injury by inhibiting apoptosis and inflammation. Hum Gene Ther 2008; 19(8): 807-19.
[http://dx.doi.org/10.1089/hum.2008.016] [PMID: 18554097]
[30]
Mohammadzadeh-Vardin M, Habibi Roudkenar M, Jahanian-Najafabadi A. Adenovirus-mediated over-expression of Nrf2 within mesenchymal Stem Cells (MSCs) protected rats against acute kidney injury. Adv Pharm Bull 2015; 5(2): 201-8.
[http://dx.doi.org/10.15171/apb.2015.028] [PMID: 26236658]
[31]
Zhaleh F, Amiri F, Mohammadzadeh-Vardin M, et al. Nuclear factor erythroid-2 related factor 2 overexpressed mesenchymal stem cells transplantation, improves renal function, decreases injuries markers and increases repair markers in glycerol-induced Acute kidney injury rats. Iran J Basic Med Sci 2016; 19(3): 323-9.
[PMID: 27114803]
[32]
Zhang F, Wan X, Cao YZ, Sun D, Cao CC. Klotho gene-modified BMSCs showed elevated antifibrotic effects by inhibiting the Wnt/β-catenin pathway in kidneys after acute injury. Cell Biol Int 2018; 42(12): 1670-9.
[http://dx.doi.org/10.1002/cbin.11068] [PMID: 30358003]
[33]
Xie LB, Chen X, Chen B, Wang XD, Jiang R, Lu YP. Protective effect of bone marrow mesenchymal stem cells modified with klotho on renal ischemia-reperfusion injury. Ren Fail 2019; 41(1): 175-82.
[http://dx.doi.org/10.1080/0886022X.2019.1588131] [PMID: 30942135]
[34]
Sahan OB, Gunel-Ozcan A. Hepatocyte growth factor and insulin-like growth Factor-1 based cellular therapies for oxidative stress injury. Curr Stem Cell Res Ther 2021; 16(7): 771-91.
[http://dx.doi.org/10.2174/1574888X16999201124153753] [PMID: 33238860]
[35]
Chen Y, Qian H, Zhu W, et al. Hepatocyte growth factor modification promotes the amelioration effects of human umbilical cord mesenchymal stem cells on rat acute kidney injury. Stem Cells Dev 2011; 20(1): 103-13.
[http://dx.doi.org/10.1089/scd.2009.0495] [PMID: 20446811]
[36]
Tögel F, Weiss K, Yang Y, Hu Z, Zhang P, Westenfelder C. Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury. Am J Physiol Renal Physiol 2007; 292(5): F1626-35.
[http://dx.doi.org/10.1152/ajprenal.00339.2006] [PMID: 17213465]
[37]
Yuan L, Wu MJ, Sun HY, et al. VEGF-modified human embryonic mesenchymal stem cell implantation enhances protection against cisplatin-induced acute kidney injury. Am J Physiol Renal Physiol 2011; 300(1): F207-18.
[http://dx.doi.org/10.1152/ajprenal.00073.2010] [PMID: 20943766]
[38]
Kamenický P, Mazziotti G, Lombès M, Giustina A, Chanson P. Growth hormone, insulin-like growth factor-1, and the kidney: Pathophysiological and clinical implications. Endocr Rev 2014; 35(2): 234-81.
[http://dx.doi.org/10.1210/er.2013-1071] [PMID: 24423979]
[39]
Imberti B, Morigi M, Tomasoni S, et al. Insulin-like growth factor-1 sustains stem cell mediated renal repair. J Am Soc Nephrol 2007; 18(11): 2921-8.
[http://dx.doi.org/10.1681/ASN.2006121318] [PMID: 17942965]
[40]
Liu P, Feng Y, Dong D, et al. Enhanced renoprotective effect of IGF-1 modified human umbilical cord-derived mesenchymal stem cells on gentamicin-induced acute kidney injury. Sci Rep 2016; 6(1): 20287.
[http://dx.doi.org/10.1038/srep20287] [PMID: 26830766]
[41]
Mishra J, Mori K, Ma Q, et al. Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 2004; 15(12): 3073-82.
[http://dx.doi.org/10.1097/01.ASN.0000145013.44578.45] [PMID: 15579510]
[42]
Roudkenar MH, Halabian R, Tehrani HA, et al. Lipocalin 2 enhances mesenchymal stem cell-based cell therapy in acute kidney injury rat model. Cytotechnology 2018; 70(1): 103-17.
[http://dx.doi.org/10.1007/s10616-017-0107-2] [PMID: 28573544]
[43]
Islam D, Huang Y, Fanelli V, et al. Identification and modulation of microenvironment is crucial for effective mesenchymal stromal cell therapy in acute lung injury. Am J Respir Crit Care Med 2019; 199(10): 1214-24.
[http://dx.doi.org/10.1164/rccm.201802-0356OC] [PMID: 30521764]
[44]
Freytes DO, Kang JW, Marcos-Campos I, Vunjak-Novakovic G. Macrophages modulate the viability and growth of human mesenchymal stem cells. J Cell Biochem 2013; 114(1): 220-9.
[http://dx.doi.org/10.1002/jcb.24357] [PMID: 22903635]
[45]
Das R, Jahr H, van Osch GJVM, Farrell E. The role of hypoxia in bone marrow-derived mesenchymal stem cells: Considerations for regenerative medicine approaches. Tissue Eng Part B Rev 2010; 16(2): 159-68.
[http://dx.doi.org/10.1089/ten.teb.2009.0296] [PMID: 19698058]
[46]
Cicione C, Muiños-López E, Hermida-Gómez T, Fuentes-Boquete I, Díaz-Prado S, Blanco FJ. Effects of severe hypoxia on bone marrow mesenchymal stem cells differentiation potential. Stem Cells Int 2013; 2013: 1-11.
[http://dx.doi.org/10.1155/2013/232896] [PMID: 24082888]
[47]
Ferreira JR, Teixeira GQ, Santos SG, Barbosa MA, Almeida-Porada G, Gonçalves RM. Mesenchymal stromal cell secretome: Influencing therapeutic potential by cellular pre-conditioning. Front Immunol 2018; 9: 2837.
[http://dx.doi.org/10.3389/fimmu.2018.02837] [PMID: 30564236]
[48]
Hung SC, Pochampally RR, Hsu SC, et al. Short-term exposure of multipotent stromal cells to low oxygen increases their expression of CX3CR1 and CXCR4 and their engraftment in vivo. PLoS One 2007; 2(5): e416.
[http://dx.doi.org/10.1371/journal.pone.0000416] [PMID: 17476338]
[49]
Palomäki S, Pietilä M, Laitinen S, et al. HIF-1α is upregulated in human mesenchymal stem cells. Stem Cells 2013; 31(9): 1902-9.
[http://dx.doi.org/10.1002/stem.1435] [PMID: 23744828]
[50]
Yu X, Lu C, Liu H, et al. Hypoxic preconditioning with cobalt of bone marrow mesenchymal stem cells improves cell migration and enhances therapy for treatment of ischemic acute kidney injury. PLoS One 2013; 8(5): e62703.
[http://dx.doi.org/10.1371/journal.pone.0062703] [PMID: 23671625]
[51]
Zhang W, Liu L, Huo Y, Yang Y, Wang Y. Hypoxia-pretreated human MSCs attenuate acute kidney injury through enhanced angiogenic and antioxidative capacities. BioMed Res Int 2014; 2014: 462472.
[http://dx.doi.org/10.1155/2014/462472] [PMID: 25133162]
[52]
Ishiuchi N, Nakashima A, Doi S, et al. Hypoxia-preconditioned mesenchymal stem cells prevent renal fibrosis and inflammation in ischemia-reperfusion rats. Stem Cell Res Ther 2020; 11(1): 130.
[http://dx.doi.org/10.1186/s13287-020-01642-6] [PMID: 32197638]
[53]
Petrenko Y, Syková E, Kubinová Š. The therapeutic potential of three-dimensional multipotent mesenchymal stromal cell spheroids. Stem Cell Res Ther 2017; 8(1): 94.
[http://dx.doi.org/10.1186/s13287-017-0558-6] [PMID: 28446248]
[54]
Zhao X, Qiu X, Zhang Y, Zhang S, Gu X, Guo H. Three-dimensional aggregates enhance the therapeutic effects of adipose mesenchymal stem cells for ischemia-reperfusion induced kidney injury in rats. Stem Cells Int 2016; 2016: 9062638.
[http://dx.doi.org/10.1155/2016/9062638] [PMID: 26649053]
[55]
Xu Y, Shi T, Xu A, Zhang L. 3D spheroid culture enhances survival and therapeutic capacities of MSC s injected into ischemic kidney. J Cell Mol Med 2016; 20(7): 1203-13.
[http://dx.doi.org/10.1111/jcmm.12651] [PMID: 26914637]
[56]
Katsuno T, Ozaki T, Saka Y, et al. Low serum cultured adipose tissue-derived stromal cells ameliorate acute kidney injury in rats. Cell Transplant 2013; 22(2): 287-97.
[http://dx.doi.org/10.3727/096368912X655019] [PMID: 22963874]
[57]
Valencia J, Blanco B, Yáñez R, et al. Comparative analysis of the immunomodulatory capacities of human bone marrow– and adipose tissue–derived mesenchymal stromal cells from the same donor. Cytotherapy 2016; 18(10): 1297-311.
[http://dx.doi.org/10.1016/j.jcyt.2016.07.006] [PMID: 27637760]
[58]
Ketterl N, Brachtl G, Schuh C, et al. A robust potency assay highlights significant donor variation of human mesenchymal stem/progenitor cell immune modulatory capacity and extended radio-resistance. Stem Cell Res Ther 2015; 6(1): 236.
[http://dx.doi.org/10.1186/s13287-015-0233-8] [PMID: 26620155]
[59]
Bloor AJC, Patel A, Griffin JE, et al. Production, safety and efficacy of iPSC-derived mesenchymal stromal cells in acute steroid-resistant graft versus host disease: a phase I, multicenter, open-label, dose-escalation study. Nat Med 2020; 26(11): 1720-5.
[http://dx.doi.org/10.1038/s41591-020-1050-x] [PMID: 32929265]
[60]
Chinnadurai R, Copland IB, Garcia MA, et al. Cryopreserved mesenchymal stromal cells are susceptible to T-Cell mediated apoptosis which is partly rescued by IFNγ licensing. Stem Cells 2016; 34(9): 2429-42.
[http://dx.doi.org/10.1002/stem.2415] [PMID: 27299362]
[61]
Oja S, Kaartinen T, Ahti M, Korhonen M, Laitinen A, Nystedt J. The utilization of freezing steps in Mesenchymal Stromal Cell (MSC) manufacturing: Potential impact on quality and cell functionality attributes. Front Immunol 2019; 10: 1627.
[http://dx.doi.org/10.3389/fimmu.2019.01627] [PMID: 31379832]
[62]
Moll G, Geißler S, Catar R, et al. Cryopreserved or fresh mesenchymal stromal cells: Only a matter of taste or key to unleash the full clinical potential of MSC therapy? Adv Exp Med Biol 2016; 951: 77-98.
[http://dx.doi.org/10.1007/978-3-319-45457-3_7] [PMID: 27837556]
[63]
Giri J, Galipeau J. Mesenchymal stromal cell therapeutic potency is dependent upon viability, route of delivery, and immune match. Blood Adv 2020; 4(9): 1987-97.
[http://dx.doi.org/10.1182/bloodadvances.2020001711] [PMID: 32384543]
[64]
Wagner W, Horn P, Castoldi M, et al. Replicative senescence of mesenchymal stem cells: A continuous and organized process. PLoS One 2008; 3(5): e2213.
[http://dx.doi.org/10.1371/journal.pone.0002213] [PMID: 18493317]
[65]
Kellum JA, Prowle JR. Paradigms of acute kidney injury in the intensive care setting. Nat Rev Nephrol 2018; 14(4): 217-30.
[http://dx.doi.org/10.1038/nrneph.2017.184] [PMID: 29355173]
[66]
Ostermann M, Wu V, Sokolov D, Lumlertgul N. Definitions of acute renal dysfunction: An evolving clinical and biomarker paradigm. Curr Opin Crit Care 2021; 27(6): 553-9.
[http://dx.doi.org/10.1097/MCC.0000000000000886] [PMID: 34535002]
[67]
Endre ZH, Mehta RL. Identification of acute kidney injury subphenotypes. Curr Opin Crit Care 2020; 26(6): 519-24.
[http://dx.doi.org/10.1097/MCC.0000000000000772] [PMID: 33044239]
[68]
Fukumitsu M, Suzuki K. Mesenchymal stem/stromal cell therapy for pulmonary arterial hypertension: Comprehensive review of preclinical studies. J Cardiol 2019; 74(4): 304-12.
[http://dx.doi.org/10.1016/j.jjcc.2019.04.006] [PMID: 31109735]
[69]
Preda MB, Lupan AM, Neculachi CA, et al. Evidence of mesenchymal stromal cell adaptation to local microenvironment following subcutaneous transplantation. J Cell Mol Med 2020; 24(18): 10889-97.
[http://dx.doi.org/10.1111/jcmm.15717] [PMID: 32785979]
[70]
Chen Y, Hu Y, Zhou X, et al. Human umbilical cord-derived mesenchymal stem cells ameliorate psoriasis-like dermatitis by suppressing IL-17-producing γδ T cells. Cell Tissue Res 2022; 388(3): 549-63.
[http://dx.doi.org/10.1007/s00441-022-03616-x] [PMID: 35347409]

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