Intrarenal Delivery of Mesenchymal Stem Cells and Endothelial Progenitor Cells Attenuates Hypertensive Cardiomyopathy in Experimental Renovascular Hypertension
Alfonso Eirin, Xiang-Yang Zhu, Behzad Ebrahimi, James D Krier, Scott M Riester, Andre J van Wijnen, Amir Lerman, Lilach O Lerman, Alfonso Eirin, Xiang-Yang Zhu, Behzad Ebrahimi, James D Krier, Scott M Riester, Andre J van Wijnen, Amir Lerman, Lilach O Lerman
Abstract
Renovascular hypertension (RVH) leads to left ventricular (LV) hypertrophy and diastolic dysfunction, associated with increased cardiovascular mortality. Intrarenal delivery of endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) improves kidney function in porcine RVH, and the potent anti-inflammatory properties of MSCs may serve to blunt inflammatory mediators in the cardiorenal axis. However, their relative efficacy in attenuating cardiac injury and dysfunction remains unknown. This study tested the hypothesis that the cardioprotective effect of EPCs and MSCs delivered into the stenotic kidney in experimental RVH are comparable. Pigs (n = 7 per group) were studied after 10 weeks of RVH or control untreated or treated with a single intrarenal infusion of autologous EPCs or MSCs 4 weeks earlier. Cardiac and renal function (fast CT) and stenotic kidney release of inflammatory mediators (ELISA) were assessed in vivo, and myocardial inflammation, remodeling, and fibrosis ex vivo. After 10 weeks of RVH, blood pressure was not altered in cell-treated groups, yet stenotic kidney glomerular filtration rate (GFR), blunted in RVH, improved in RVH + EPC, and normalized in RVH + MSCs. Stenotic kidney release of monocyte chemoattractant protein (MCP)-1 and its myocardial expression were elevated in RVH + EPC, but normalized only in RVH + MSC pigs. RVH-induced LV hypertrophy was normalized in both EPC- and MSC-treated pigs, while diastolic function (E/A ratio) was restored to normal levels exclusively in RVH + MSCs. RVH-induced myocardial fibrosis and collagen deposition decreased in RVH + EPCs but further decreased in RVH + MSC-treated pigs. Intrarenal delivery of EPCs or MSCs attenuates RVH-induced myocardial injury, yet MSCs restore diastolic function more effectively than EPCs, possibly by greater improvement in renal function or reduction of MCP-1 release from the stenotic kidney. These observations suggest a therapeutic potential for EPCs and MSCs in preserving the myocardium in chronic experimental RVH.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4440858/bin/nihms673953f1.jpg)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4440858/bin/nihms673953f2.jpg)
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4440858/bin/nihms673953f3.jpg)
Figure 4
Myocardium double immunofluorescence staining of…
Figure 4
Myocardium double immunofluorescence staining of connexin-43 (green) and the inflammatory mediators (red): interferon…
Figure 5
A: Myocyte cross-sectional area (H&E,…
Figure 5
A: Myocyte cross-sectional area (H&E, 40×) and its quantification. B: Representative immunostaining and…
Figure 6
A: Renal blood flow (RBF),…
Figure 6
A: Renal blood flow (RBF), and glomerular filtration rate (GFR) in the contralateral…
- Intra-renal delivery of mesenchymal stem cells attenuates myocardial injury after reversal of hypertension in porcine renovascular disease.Eirin A, Zhu XY, Ferguson CM, Riester SM, van Wijnen AJ, Lerman A, Lerman LO. Eirin A, et al. Stem Cell Res Ther. 2015 Jan 19;6(1):7. doi: 10.1186/scrt541. Stem Cell Res Ther. 2015. PMID: 25599803 Free PMC article.
- Selective intrarenal delivery of mesenchymal stem cell-derived extracellular vesicles attenuates myocardial injury in experimental metabolic renovascular disease.Zhang L, Zhu XY, Zhao Y, Eirin A, Liu L, Ferguson CM, Tang H, Lerman A, Lerman LO. Zhang L, et al. Basic Res Cardiol. 2020 Jan 14;115(2):16. doi: 10.1007/s00395-019-0772-8. Basic Res Cardiol. 2020. PMID: 31938859 Free PMC article.
- IL-10 partly mediates the ability of MSC-derived extracellular vesicles to attenuate myocardial damage in experimental metabolic renovascular hypertension.Jiang Y, Hong S, Zhu X, Zhang L, Tang H, Jordan KL, Saadiq IM, Huang W, Lerman A, Eirin A, Lerman LO. Jiang Y, et al. Front Immunol. 2022 Sep 20;13:940093. doi: 10.3389/fimmu.2022.940093. eCollection 2022. Front Immunol. 2022. PMID: 36203611 Free PMC article.
- Enhanced endothelial progenitor cell angiogenic potency, present in early experimental renovascular hypertension, deteriorates with disease duration.Zhu XY, Urbieta Caceres VH, Favreau FD, Krier JD, Lerman A, Lerman LO. Zhu XY, et al. J Hypertens. 2011 Oct;29(10):1972-9. doi: 10.1097/HJH.0b013e32834ae611. J Hypertens. 2011. PMID: 21873884 Free PMC article.
- Restoration of Mitochondrial Cardiolipin Attenuates Cardiac Damage in Swine Renovascular Hypertension.Eirin A, Ebrahimi B, Kwon SH, Fiala JA, Williams BJ, Woollard JR, He Q, Gupta RC, Sabbah HN, Prakash YS, Textor SC, Lerman A, Lerman LO. Eirin A, et al. J Am Heart Assoc. 2016 May 31;5(6):e003118. doi: 10.1161/JAHA.115.003118. J Am Heart Assoc. 2016. PMID: 27247333 Free PMC article.
- Mesenchymal Stem Cells and Their Exocytotic Vesicles.Cai H, Guo H. Cai H, et al. Int J Mol Sci. 2023 Jan 20;24(3):2085. doi: 10.3390/ijms24032085. Int J Mol Sci. 2023. PMID: 36768406 Free PMC article. Review.
- Autologous Extracellular Vesicles Attenuate Cardiac Injury in Experimental Atherosclerotic Renovascular Disease More Effectively Than Their Parent Mesenchymal Stem/Stromal Cells.Hong S, Zhu XY, Jiang Y, Zhang L, Tang H, Jordan KL, Saadiq IM, Huang W, Lerman A, Eirin A, Lerman LO. Hong S, et al. Stem Cell Rev Rep. 2023 Apr;19(3):700-712. doi: 10.1007/s12015-022-10473-2. Epub 2022 Nov 7. Stem Cell Rev Rep. 2023. PMID: 36344721
- Effects of mesenchymal stem cells in renovascular disease of preclinical and clinical studies: a systematic review and meta-analysis.Wang HS, Yi MY, Wu X, Liu Q, Deng YH, Wu T, Wang L, Kang YX, Luo XQ, Yan P, Wang M, Duan SB. Wang HS, et al. Sci Rep. 2022 Oct 27;12(1):18080. doi: 10.1038/s41598-022-23059-2. Sci Rep. 2022. PMID: 36302933 Free PMC article.
- Cardiovascular Effects of Autologous Bone Marrow-Derived Mesenchymal Stromal Cell Therapy With Early Tacrolimus Withdrawal in Renal Transplant Recipients: An Analysis of the Randomized TRITON Study.Meucci MC, Reinders MEJ, Groeneweg KE, Bezstarosti S, Ajmone Marsan N, Bax JJ, De Fijter JW, Delgado V. Meucci MC, et al. J Am Heart Assoc. 2021 Dec 21;10(24):e023300. doi: 10.1161/JAHA.121.023300. Epub 2021 Dec 16. J Am Heart Assoc. 2021. PMID: 34913362 Free PMC article. Clinical Trial.
- Progress toward the Clinical Application of Mesenchymal Stromal Cells and Other Disease-Modulating Regenerative Therapies: Examples from the Field of Nephrology.Hickson LJ, Herrmann SM, McNicholas BA, Griffin MD. Hickson LJ, et al. Kidney360. 2021 Mar;2(3):542-557. doi: 10.34067/KID.0005692020. Kidney360. 2021. PMID: 34316720 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Animals
- Blood Pressure / physiology
- Cardiomyopathies / pathology*
- Disease Models, Animal
- Endothelial Progenitor Cells / cytology*
- Heart / physiopathology
- Hypertension, Renovascular / therapy*
- Kidney / pathology
- Mesenchymal Stem Cell Transplantation* / methods
- Mesenchymal Stem Cells / cytology*
- Myocardium / metabolism
- Swine
- R01 HL123160/HL/NHLBI NIH HHS/United States
- R01 AG031750/AG/NIA NIH HHS/United States
- R21 HL121561/HL/NHLBI NIH HHS/United States
- R01 DK100081/DK/NIDDK NIH HHS/United States
- DK73608/DK/NIDDK NIH HHS/United States
- DK104273/DK/NIDDK NIH HHS/United States
- HL121561/HL/NHLBI NIH HHS/United States
- UL1 TR000135/TR/NCATS NIH HHS/United States
- R01 DK073608/DK/NIDDK NIH HHS/United States
- AG31750/AG/NIA NIH HHS/United States
- K01 RR000135/RR/NCRR NIH HHS/United States
- U01 DK104273/DK/NIDDK NIH HHS/United States
- DK100081/DK/NIDDK NIH HHS/United States
- R01 DK102325/DK/NIDDK NIH HHS/United States
- UL1-RR000135/RR/NCRR NIH HHS/United States
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 4](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4440858/bin/nihms673953f4.jpg)
Figure 5
A: Myocyte cross-sectional area (H&E,…
Figure 5
A: Myocyte cross-sectional area (H&E, 40×) and its quantification. B: Representative immunostaining and…
Figure 6
A: Renal blood flow (RBF),…
Figure 6
A: Renal blood flow (RBF), and glomerular filtration rate (GFR) in the contralateral…
- Intra-renal delivery of mesenchymal stem cells attenuates myocardial injury after reversal of hypertension in porcine renovascular disease.Eirin A, Zhu XY, Ferguson CM, Riester SM, van Wijnen AJ, Lerman A, Lerman LO. Eirin A, et al. Stem Cell Res Ther. 2015 Jan 19;6(1):7. doi: 10.1186/scrt541. Stem Cell Res Ther. 2015. PMID: 25599803 Free PMC article.
- Selective intrarenal delivery of mesenchymal stem cell-derived extracellular vesicles attenuates myocardial injury in experimental metabolic renovascular disease.Zhang L, Zhu XY, Zhao Y, Eirin A, Liu L, Ferguson CM, Tang H, Lerman A, Lerman LO. Zhang L, et al. Basic Res Cardiol. 2020 Jan 14;115(2):16. doi: 10.1007/s00395-019-0772-8. Basic Res Cardiol. 2020. PMID: 31938859 Free PMC article.
- IL-10 partly mediates the ability of MSC-derived extracellular vesicles to attenuate myocardial damage in experimental metabolic renovascular hypertension.Jiang Y, Hong S, Zhu X, Zhang L, Tang H, Jordan KL, Saadiq IM, Huang W, Lerman A, Eirin A, Lerman LO. Jiang Y, et al. Front Immunol. 2022 Sep 20;13:940093. doi: 10.3389/fimmu.2022.940093. eCollection 2022. Front Immunol. 2022. PMID: 36203611 Free PMC article.
- Enhanced endothelial progenitor cell angiogenic potency, present in early experimental renovascular hypertension, deteriorates with disease duration.Zhu XY, Urbieta Caceres VH, Favreau FD, Krier JD, Lerman A, Lerman LO. Zhu XY, et al. J Hypertens. 2011 Oct;29(10):1972-9. doi: 10.1097/HJH.0b013e32834ae611. J Hypertens. 2011. PMID: 21873884 Free PMC article.
- Restoration of Mitochondrial Cardiolipin Attenuates Cardiac Damage in Swine Renovascular Hypertension.Eirin A, Ebrahimi B, Kwon SH, Fiala JA, Williams BJ, Woollard JR, He Q, Gupta RC, Sabbah HN, Prakash YS, Textor SC, Lerman A, Lerman LO. Eirin A, et al. J Am Heart Assoc. 2016 May 31;5(6):e003118. doi: 10.1161/JAHA.115.003118. J Am Heart Assoc. 2016. PMID: 27247333 Free PMC article.
- Mesenchymal Stem Cells and Their Exocytotic Vesicles.Cai H, Guo H. Cai H, et al. Int J Mol Sci. 2023 Jan 20;24(3):2085. doi: 10.3390/ijms24032085. Int J Mol Sci. 2023. PMID: 36768406 Free PMC article. Review.
- Autologous Extracellular Vesicles Attenuate Cardiac Injury in Experimental Atherosclerotic Renovascular Disease More Effectively Than Their Parent Mesenchymal Stem/Stromal Cells.Hong S, Zhu XY, Jiang Y, Zhang L, Tang H, Jordan KL, Saadiq IM, Huang W, Lerman A, Eirin A, Lerman LO. Hong S, et al. Stem Cell Rev Rep. 2023 Apr;19(3):700-712. doi: 10.1007/s12015-022-10473-2. Epub 2022 Nov 7. Stem Cell Rev Rep. 2023. PMID: 36344721
- Effects of mesenchymal stem cells in renovascular disease of preclinical and clinical studies: a systematic review and meta-analysis.Wang HS, Yi MY, Wu X, Liu Q, Deng YH, Wu T, Wang L, Kang YX, Luo XQ, Yan P, Wang M, Duan SB. Wang HS, et al. Sci Rep. 2022 Oct 27;12(1):18080. doi: 10.1038/s41598-022-23059-2. Sci Rep. 2022. PMID: 36302933 Free PMC article.
- Cardiovascular Effects of Autologous Bone Marrow-Derived Mesenchymal Stromal Cell Therapy With Early Tacrolimus Withdrawal in Renal Transplant Recipients: An Analysis of the Randomized TRITON Study.Meucci MC, Reinders MEJ, Groeneweg KE, Bezstarosti S, Ajmone Marsan N, Bax JJ, De Fijter JW, Delgado V. Meucci MC, et al. J Am Heart Assoc. 2021 Dec 21;10(24):e023300. doi: 10.1161/JAHA.121.023300. Epub 2021 Dec 16. J Am Heart Assoc. 2021. PMID: 34913362 Free PMC article. Clinical Trial.
- Progress toward the Clinical Application of Mesenchymal Stromal Cells and Other Disease-Modulating Regenerative Therapies: Examples from the Field of Nephrology.Hickson LJ, Herrmann SM, McNicholas BA, Griffin MD. Hickson LJ, et al. Kidney360. 2021 Mar;2(3):542-557. doi: 10.34067/KID.0005692020. Kidney360. 2021. PMID: 34316720 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Animals
- Blood Pressure / physiology
- Cardiomyopathies / pathology*
- Disease Models, Animal
- Endothelial Progenitor Cells / cytology*
- Heart / physiopathology
- Hypertension, Renovascular / therapy*
- Kidney / pathology
- Mesenchymal Stem Cell Transplantation* / methods
- Mesenchymal Stem Cells / cytology*
- Myocardium / metabolism
- Swine
- R01 HL123160/HL/NHLBI NIH HHS/United States
- R01 AG031750/AG/NIA NIH HHS/United States
- R21 HL121561/HL/NHLBI NIH HHS/United States
- R01 DK100081/DK/NIDDK NIH HHS/United States
- DK73608/DK/NIDDK NIH HHS/United States
- DK104273/DK/NIDDK NIH HHS/United States
- HL121561/HL/NHLBI NIH HHS/United States
- UL1 TR000135/TR/NCATS NIH HHS/United States
- R01 DK073608/DK/NIDDK NIH HHS/United States
- AG31750/AG/NIA NIH HHS/United States
- K01 RR000135/RR/NCRR NIH HHS/United States
- U01 DK104273/DK/NIDDK NIH HHS/United States
- DK100081/DK/NIDDK NIH HHS/United States
- R01 DK102325/DK/NIDDK NIH HHS/United States
- UL1-RR000135/RR/NCRR NIH HHS/United States
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 5](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4440858/bin/nihms673953f5.jpg)
Figure 6
A: Renal blood flow (RBF),…
Figure 6
A: Renal blood flow (RBF), and glomerular filtration rate (GFR) in the contralateral…
- Intra-renal delivery of mesenchymal stem cells attenuates myocardial injury after reversal of hypertension in porcine renovascular disease.Eirin A, Zhu XY, Ferguson CM, Riester SM, van Wijnen AJ, Lerman A, Lerman LO. Eirin A, et al. Stem Cell Res Ther. 2015 Jan 19;6(1):7. doi: 10.1186/scrt541. Stem Cell Res Ther. 2015. PMID: 25599803 Free PMC article.
- Selective intrarenal delivery of mesenchymal stem cell-derived extracellular vesicles attenuates myocardial injury in experimental metabolic renovascular disease.Zhang L, Zhu XY, Zhao Y, Eirin A, Liu L, Ferguson CM, Tang H, Lerman A, Lerman LO. Zhang L, et al. Basic Res Cardiol. 2020 Jan 14;115(2):16. doi: 10.1007/s00395-019-0772-8. Basic Res Cardiol. 2020. PMID: 31938859 Free PMC article.
- IL-10 partly mediates the ability of MSC-derived extracellular vesicles to attenuate myocardial damage in experimental metabolic renovascular hypertension.Jiang Y, Hong S, Zhu X, Zhang L, Tang H, Jordan KL, Saadiq IM, Huang W, Lerman A, Eirin A, Lerman LO. Jiang Y, et al. Front Immunol. 2022 Sep 20;13:940093. doi: 10.3389/fimmu.2022.940093. eCollection 2022. Front Immunol. 2022. PMID: 36203611 Free PMC article.
- Enhanced endothelial progenitor cell angiogenic potency, present in early experimental renovascular hypertension, deteriorates with disease duration.Zhu XY, Urbieta Caceres VH, Favreau FD, Krier JD, Lerman A, Lerman LO. Zhu XY, et al. J Hypertens. 2011 Oct;29(10):1972-9. doi: 10.1097/HJH.0b013e32834ae611. J Hypertens. 2011. PMID: 21873884 Free PMC article.
- Restoration of Mitochondrial Cardiolipin Attenuates Cardiac Damage in Swine Renovascular Hypertension.Eirin A, Ebrahimi B, Kwon SH, Fiala JA, Williams BJ, Woollard JR, He Q, Gupta RC, Sabbah HN, Prakash YS, Textor SC, Lerman A, Lerman LO. Eirin A, et al. J Am Heart Assoc. 2016 May 31;5(6):e003118. doi: 10.1161/JAHA.115.003118. J Am Heart Assoc. 2016. PMID: 27247333 Free PMC article.
- Mesenchymal Stem Cells and Their Exocytotic Vesicles.Cai H, Guo H. Cai H, et al. Int J Mol Sci. 2023 Jan 20;24(3):2085. doi: 10.3390/ijms24032085. Int J Mol Sci. 2023. PMID: 36768406 Free PMC article. Review.
- Autologous Extracellular Vesicles Attenuate Cardiac Injury in Experimental Atherosclerotic Renovascular Disease More Effectively Than Their Parent Mesenchymal Stem/Stromal Cells.Hong S, Zhu XY, Jiang Y, Zhang L, Tang H, Jordan KL, Saadiq IM, Huang W, Lerman A, Eirin A, Lerman LO. Hong S, et al. Stem Cell Rev Rep. 2023 Apr;19(3):700-712. doi: 10.1007/s12015-022-10473-2. Epub 2022 Nov 7. Stem Cell Rev Rep. 2023. PMID: 36344721
- Effects of mesenchymal stem cells in renovascular disease of preclinical and clinical studies: a systematic review and meta-analysis.Wang HS, Yi MY, Wu X, Liu Q, Deng YH, Wu T, Wang L, Kang YX, Luo XQ, Yan P, Wang M, Duan SB. Wang HS, et al. Sci Rep. 2022 Oct 27;12(1):18080. doi: 10.1038/s41598-022-23059-2. Sci Rep. 2022. PMID: 36302933 Free PMC article.
- Cardiovascular Effects of Autologous Bone Marrow-Derived Mesenchymal Stromal Cell Therapy With Early Tacrolimus Withdrawal in Renal Transplant Recipients: An Analysis of the Randomized TRITON Study.Meucci MC, Reinders MEJ, Groeneweg KE, Bezstarosti S, Ajmone Marsan N, Bax JJ, De Fijter JW, Delgado V. Meucci MC, et al. J Am Heart Assoc. 2021 Dec 21;10(24):e023300. doi: 10.1161/JAHA.121.023300. Epub 2021 Dec 16. J Am Heart Assoc. 2021. PMID: 34913362 Free PMC article. Clinical Trial.
- Progress toward the Clinical Application of Mesenchymal Stromal Cells and Other Disease-Modulating Regenerative Therapies: Examples from the Field of Nephrology.Hickson LJ, Herrmann SM, McNicholas BA, Griffin MD. Hickson LJ, et al. Kidney360. 2021 Mar;2(3):542-557. doi: 10.34067/KID.0005692020. Kidney360. 2021. PMID: 34316720 Free PMC article. Review.
- Research Support, N.I.H., Extramural
- Animals
- Blood Pressure / physiology
- Cardiomyopathies / pathology*
- Disease Models, Animal
- Endothelial Progenitor Cells / cytology*
- Heart / physiopathology
- Hypertension, Renovascular / therapy*
- Kidney / pathology
- Mesenchymal Stem Cell Transplantation* / methods
- Mesenchymal Stem Cells / cytology*
- Myocardium / metabolism
- Swine
- R01 HL123160/HL/NHLBI NIH HHS/United States
- R01 AG031750/AG/NIA NIH HHS/United States
- R21 HL121561/HL/NHLBI NIH HHS/United States
- R01 DK100081/DK/NIDDK NIH HHS/United States
- DK73608/DK/NIDDK NIH HHS/United States
- DK104273/DK/NIDDK NIH HHS/United States
- HL121561/HL/NHLBI NIH HHS/United States
- UL1 TR000135/TR/NCATS NIH HHS/United States
- R01 DK073608/DK/NIDDK NIH HHS/United States
- AG31750/AG/NIA NIH HHS/United States
- K01 RR000135/RR/NCRR NIH HHS/United States
- U01 DK104273/DK/NIDDK NIH HHS/United States
- DK100081/DK/NIDDK NIH HHS/United States
- R01 DK102325/DK/NIDDK NIH HHS/United States
- UL1-RR000135/RR/NCRR NIH HHS/United States
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
![Figure 6](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4440858/bin/nihms673953f6.jpg)
Source: PubMed