Abstract
Introduction
Obesity is a health burden that impairs cellular processes. Mesenchymal stem/stromal cells (MSCs) are endowed with reparative properties and can ameliorate renal injury. Obesity impairs human MSC function in-vitro, but its effect on their in-vivo reparative potency remains unknown.
Subjects and methods
Abdominal adipose tissue-derived MSC were harvested from patients without (‘lean’) or with obesity (‘obese’) (body mass index <30 or ≥30 kg/m2, respectively) during kidney donation or bariatric surgery, respectively. MSC (5 × 105/200 µL) or vehicle were then injected into 129S1 mice 2 weeks after renal artery stenosis (RAS) or sham surgery (n = 8/group). Two weeks later, mice underwent magnetic resonance imaging to assess renal perfusion and oxygenation in-vivo, and kidneys then harvested for ex-vivo studies.
Results
Similar numbers of lean and obese-MSCs engrafted in stenotic mouse kidneys. Vehicle-treated RAS mice had reduced stenotic-kidney cortical and medullary perfusion and oxygenation. Lean (but not obese) MSC normalized ischemic kidney cortical perfusion, whereas both effectively mitigated renal hypoxia. Serum creatinine and blood pressure were elevated in RAS mice and lowered only by lean-MSC. Both types of MSCs alleviated stenotic-kidney fibrosis, but lean-MSC more effectively than obese-MSC. MSC senescence-associated beta-gal activity, and gene expression of p16, p21, and vascular endothelial growth factor correlated with recipient kidney perfusion and tissue injury, linking MSC characteristics with their in-vivo reparative capacity.
Discussion
Human obesity impairs the reparative properties of adipose-tissue-derived MSCs, possibly by inducing cellular senescence. Dysfunction and senescence of the endogenous MSC repair system in patients with obesity may warrant targeting interventions to restore MSC vitality.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Han Y, Li X, Zhang Y, Han Y, Chang F, Ding J. Mesenchymal stem cells for regenerative medicine. Cells. 2019;8, https://doi.org/10.3390/cells8080886.
Schneider S, Unger M, van Griensven M, Balmayor ER. Adipose-derived mesenchymal stem cells from liposuction and resected fat are feasible sources for regenerative medicine. Eur J Med Res. 2017;22:17 https://doi.org/10.1186/s40001-017-0258-9.
Hickson LJ, Eirin A, Lerman LO. Challenges and opportunities for stem cell therapy in patients with chronic kidney disease. Kidney Int. 2016;89:767–78. https://doi.org/10.1016/j.kint.2015.11.023.
Ebrahimi B, Eirin A, Li Z, Zhu XY, Zhang X, Lerman A, et al. Mesenchymal stem cells improve medullary inflammation and fibrosis after revascularization of swine atherosclerotic renal artery stenosis. PLoS One. 2013;8:e67474 https://doi.org/10.1371/journal.pone.0067474
Eirin A, Zhu XY, Krier JD, Tang H, Jordan KL, Grande JP, et al. Adipose tissue-derived mesenchymal stem cells improve revascularization outcomes to restore renal function in swine atherosclerotic renal artery stenosis. Stem Cells. 2012;30:1030–41. https://doi.org/10.1002/stem.1047.
Zhu XY, Urbieta-Caceres V, Krier JD, Textor SC, Lerman A, Lerman LO. Mesenchymal stem cells and endothelial progenitor cells decrease renal injury in experimental swine renal artery stenosis through different mechanisms. Stem Cells. 2013;31:117–25. https://doi.org/10.1002/stem.1263.
Zou X, Jiang K, Puranik AS, Jordan KL, Tang H, Zhu XY, et al. Targeting murine mesenchymal stem cells to kidney injury molecule-1 improves their therapeutic efficacy in chronic ischemic kidney injury. Stem Cells Transl Med. 2018;7:394–403. https://doi.org/10.1002/sctm.17-0186.
Saad A, Dietz AB, Herrmann SMS, Hickson LJ, Glockner JA, McKusick MA, et al. Autologous mesenchymal stem cells increase cortical perfusion in renovascular disease. J Am Soc Nephrol. 2017;28:2777–85. https://doi.org/10.1681/asn.2017020151.
Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014;32:252–60. https://doi.org/10.1038/nbt.2816.
Engin A. The definition and prevalence of obesity and metabolic syndrome. Adv Exp Med Biol. 2017;960:1–17. https://doi.org/10.1007/978-3-319-48382-5_1
de Heredia FP, Gómez-Martínez S, Marcos A. Obesity, inflammation and the immune system. Proc Nutr Soc. 2012;71:332–8. https://doi.org/10.1017/s0029665112000092.
Liu Z, Wu KKL, Jiang X, Xu A, Cheng KKY. The role of adipose tissue senescence in obesity- and ageing-related metabolic disorders. Clin Sci. 2020;134:315–30. https://doi.org/10.1042/cs20190966.
Turinetto V, Vitale E, Giachino C. Senescence in human mesenchymal stem cells: functional changes and implications in stem cell-based therapy. Int J Mol Sci. 2016;17, https://doi.org/10.3390/ijms17071164.
Conley SM, Hickson LJ, Kellogg TA, McKenzie T, Heimbach JK, Taner T, et al. Human obesity induces dysfunction and early senescence in adipose tissue-derived mesenchymal stromal/stem cells. Front Cell Dev Biol. 2020;8:197 https://doi.org/10.3389/fcell.2020.00197.
Conley SM, Shook JE, Zhu XY, Eirin A, Jordan KL, Woollard JR, et al. Metabolic syndrome induces release of smaller extracellular vesicles from porcine mesenchymal stem cells. Cell Transplant. 2019;28:1271–8. https://doi.org/10.1177/0963689719860840.
Eirin A, Zhu XY, Woollard JR, Tang H, Dasari S, Lerman A, et al. Metabolic syndrome interferes with packaging of proteins within porcine mesenchymal stem cell-derived extracellular vesicles. Stem Cells Transl Med. 2019;8:430–40. https://doi.org/10.1002/sctm.18-0171.
Pawar AS, Eirin A, Krier JD, Woollard JR, Zhu XY, Lerman A, et al. Alterations in genetic and protein content of swine adipose tissue-derived mesenchymal stem cells in the metabolic syndrome. Stem Cell Res. 2019;37:101423 https://doi.org/10.1016/j.scr.2019.101423.
Zhu XY, Ma S, Eirin A, Woollard JR, Hickson LJ, Sun D, et al. Functional plasticity of adipose-derived stromal cells during development of obesity. Stem Cells Transl Med. 2016;5:893–900. https://doi.org/10.5966/sctm.2015-0240.
Jiang K, Tang H, Mishra PK, Macura SI, Lerman LO. Measurement of murine single-kidney glomerular filtration rate using dynamic contrast-enhanced MRI. Magn Reson Med. 2018;79:2935–43. https://doi.org/10.1002/mrm.26955.
Jiang K, Ferguson CM, Ebrahimi B, Tang H, Kline TL, Burningham TA, et al. Noninvasive assessment of renal fibrosis with magnetization transfer MR imaging: validation and evaluation in murine renal artery stenosis. Radiology. 2017;283:77–86. https://doi.org/10.1148/radiol.2016160566.
Bongoni AK, Lu B, Salvaris EJ, Roberts V, Fang D, McRae JL, et al. Overexpression of human CD55 and CD59 or treatment with human CD55 protects against renal ischemia-reperfusion injury in mice. J Immunol. 2017;198:4837–45. https://doi.org/10.4049/jimmunol.1601943.
Pierpont YN, Dinh TP, Salas RE, Johnson EL, Wright TG, Robson MC, et al. Obesity and surgical wound healing: a current review. ISRN Obes. 2014;2014:638936 https://doi.org/10.1155/2014/638936.
Papazova DA, Oosterhuis NR, Gremmels H, van Koppen A, Joles JA, Verhaar MC. Cell-based therapies for experimental chronic kidney disease: a systematic review and meta-analysis. Dis Models Mech. 2015;8:281–93. https://doi.org/10.1242/dmm.017699.
Aghajani Nargesi A, Lerman LO, Eirin A. Mesenchymal stem cell-derived extracellular vesicles for kidney repair: current status and looming challenges. Stem Cell Res Therapy. 2017;8:273 https://doi.org/10.1186/s13287-017-0727-7.
Saad A, Zhu XY, Herrmann S, Hickson LJ, Tang H, Dietz AB, et al. Adipose-derived mesenchymal stem cells from patients with atherosclerotic renovascular disease have increased DNA damage and reduced angiogenesis that can be modified by hypoxia. Stem Cell Res Ther. 2016;7:128 https://doi.org/10.1186/s13287-016-0389-x.
Oliva-Olivera W, Coín-Aragüez L, Lhamyani S, Clemente-Postigo M, Alcaide Torres J, Bernal-Lopez MR, et al. Adipogenic impairment of adipose tissue-derived mesenchymal stem cells in subjects with metabolic syndrome: possible protective role of FGF2. J Clin Endocrinol Metab. 2017;102:478–87. https://doi.org/10.1210/jc.2016-2256.
Meng Y, Eirin A, Zhu XY, Tang H, Chanana P, Lerman A, et al. Obesity-induced mitochondrial dysfunction in porcine adipose tissue-derived mesenchymal stem cells. J Cell Physiol. 2018;233:5926–36. https://doi.org/10.1002/jcp.26402.
Meng Y, Eirin A, Zhu XY, Tang H, Chanana P, Lerman A, et al. The metabolic syndrome alters the miRNA signature of porcine adipose tissue-derived mesenchymal stem cells. Cytometry A. 2018;93:93–103. https://doi.org/10.1002/cyto.a.23165.
Aghajani Nargesi A, Zhu XY, Hickson LJ, Conley SM, van Wijnen AJ, Lerman LO, et al. Metabolic syndrome modulates protein import into the mitochondria of porcine mesenchymal stem cells. Stem Cell Rev Rep. 2019;15:427–38. https://doi.org/10.1007/s12015-018-9855-4.
Nadeau S, Cheng A, Colmegna I, Rodier F. Quantifying senescence-associated phenotypes in primary multipotent mesenchymal stromal cell cultures. Methods Mol Biol. 2019;2045:93–105. https://doi.org/10.1007/7651_2019_217.
Liu JY, Souroullas GP, Diekman BO, Krishnamurthy J, Hall BM, Sorrentino JA, et al. Cells exhibiting strong p16 (INK4a) promoter activation in vivo display features of senescence. Proc Natl Acad Sci USA. 2019;116:2603–11. https://doi.org/10.1073/pnas.1818313116.
Kim SR, Puranik AS, Jiang K, Chen XJ, Zhu XY, Taylor I, et al. Progressive cellular senescence mediates renal dysfunction in ischemic nephropathy. J Am Soc Nephrol. 2021;32:1987–2004. https://doi.org/10.1681/asn.2020091373.
Kim SR, Zou X, Tang H, Puranik AS, Abumoawad AM, Zhu XY, et al. Increased cellular senescence in the murine and human stenotic kidney: effect of mesenchymal stem cells. J Cell Physiol. 2021;236:1332–44. https://doi.org/10.1002/jcp.29940.
Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118. https://doi.org/10.1146/annurev-pathol-121808-102144.
Sturmlechner I, Durik M, Sieben CJ, Baker DJ, van Deursen JM. Cellular senescence in renal ageing and disease. Nat Rev Nephrol. 2017;13:77–89. https://doi.org/10.1038/nrneph.2016.183.
Chade AR, Tullos NA, Harvey TW, Mahdi F, Bidwell GL 3rd. Renal therapeutic angiogenesis using a bioengineered polymer-stabilized vascular endothelial growth factor construct. J Am Soc Nephrol. 2016;27:1741–52. https://doi.org/10.1681/asn.2015040346.
Suvakov S, Cubro H, White WM, Butler Tobah YS, Weissgerber TL, Joradn KL, et al. Targeting senescence improves angiogenic potential of adipose-derived mesenchymal stem cells in patients with preeclampsia. Biol Sex Differ. 2019;10:49 https://doi.org/10.1186/s13293-019-0263-5.
Lerman LO, Textor SC, Grande JP. Mechanisms of tissue injury in renal artery stenosis: ischemia and beyond. Prog Cardiovasc Dis. 2009;52:196–203. https://doi.org/10.1016/j.pcad.2009.09.002.
Textor SC, Lerman LO. The role of hypoxia in ischemic chronic kidney disease. Semin Nephrol. 2019;39:589–98. https://doi.org/10.1016/j.semnephrol.2019.10.008.
Eirin A, Zhu XY, Puranik AS, Tang H, McGurren KA, van Wijnen AJ, et al. Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation. Kidney Int. 2017;92:114–24. https://doi.org/10.1016/j.kint.2016.12.023.
Chen XJ, Zhang X, Jiang K, Krier JD, Zhu XY, Conley S, et al. Adjunctive mesenchymal stem/stromal cells augment microvascular function in poststenotic kidneys treated with low-energy shockwave therapy. J Cell Physiol. 2020;235:9806–18. https://doi.org/10.1002/jcp.29794.
Eirin A, Zhang X, Zhu XY, Tang H, Jordan KL, Grande JP, et al. Renal vein cytokine release as an index of renal parenchymal inflammation in chronic experimental renal artery stenosis. Nephrol Dial Transplant. 2014;29:274–82. https://doi.org/10.1093/ndt/gft305.
Zhao Y, Zhu XY, Song T, Zhang L, Eirin A, Conley S, et al. Mesenchymal stem cells protect renal tubular cells via TSG-6 regulating macrophage function and phenotype switching. Am J Physiol Renal Physiol. 2021;320:F454–f463. https://doi.org/10.1152/ajprenal.00426.2020.
Song T, Eirin A, Zhu XY, Zhao Y, Krier JD, Tang H, et al. Mesenchymal stem cell-derived extracellular vesicles induce regulatory T cells to ameliorate chronic kidney injury. Hypertension. 2020;75:1223–32. https://doi.org/10.1161/hypertensionaha.119.14546.
Eirin A, Ferguson CM, Zhu XY, Saadiq I, Tang H, Lerman A, et al. Extracellular vesicles released by adipose tissue-derived mesenchymal stromal/stem cells from obese pigs fail to repair the injured kidney. Stem Cell Res. 2020;47:101877 https://doi.org/10.1016/j.scr.2020.101877.
Saleem M, Saavedra-Sánchez L, Barturen-Larrea P, Gomez JA. The transcription factor Sox6 controls renin expression during renal artery stenosis. Kidney360. 2021. https://doi.org/10.34067/kid.0002792020.
Melk A, Schmidt BM, Takeuchi O, Sawitzki B, Rayner DC, Halloran PF. Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney Int. 2004;65:510–20. https://doi.org/10.1111/j.1523-1755.2004.00438.x.
Chen XJ, Kim SR, Jiang K, Ferguson C, Tang H, Zhu XY, et al. Renovascular disease induces senescence in renal scattered tubular-like cells and impairs their reparative potency. Hypertension. 2021;77:507–18. https://doi.org/10.1161/hypertensionaha.120.16218.
Kim SR, Jiang K, Ferguson CM, Tang H, Chen XJ, Zhu XY, et al. Transplanted senescent renal scattered tubular-like cells induce injury in the mouse kidney. Am J Physiol Renal Physiol. 2020;318:F1167–f1176. https://doi.org/10.1152/ajprenal.00535.2019.
Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringdén O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol. 2003;31:890–6. https://doi.org/10.1016/s0301-472x(03)00110-3.
von Bahr L, Batsis I, Moll G, Hagg M, Szakos A, Sundberg B, et al. Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells. 2012;30:1575–8. https://doi.org/10.1002/stem.1118.
Bonab MM, Alimoghaddam K, Talebian F, Ghaffari SH, Ghavamzadeh A, Nikbin B. Aging of mesenchymal stem cell in vitro. BMC Cell Biol. 2006;7:14 https://doi.org/10.1186/1471-2121-7-14.
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NK: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; SMC: provision of study material, collection and assembly of data; XZ: conception and design, provision of study material, collection and assembly of data; IMS: provisional of study material, collection and assembly of data, YL: collection and assembly of data, data analysis an interpretation; JDK: administrative support, provisional of study material, collection and assembly of data; CMF: administrative support, provisional of study material, collection and assembly of data; KLJ: provisional of study material, collection and assembly of data; HT: provisional of study material, collection and assembly of data; AL: data interpretation, manuscript writing; LOL: conception and design, financial support, administrative support, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript
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This study was partly supported by NIH grant numbers DK120292, DK122734, and AG062104. LOL is an advisor to AstraZeneca, CureSpec, and Butterfly Biosciences. All authors declare no conflict of interest.
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Klomjit, N., Conley, S.M., Zhu, X.Y. et al. Effects of obesity on reparative function of human adipose tissue-derived mesenchymal stem cells on ischemic murine kidneys. Int J Obes 46, 1222–1233 (2022). https://doi.org/10.1038/s41366-022-01103-5
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DOI: https://doi.org/10.1038/s41366-022-01103-5
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