Allogeneic Mesenchymal Stem Cells Restore Endothelial Function in Heart Failure by Stimulating Endothelial Progenitor Cells

Courtney Premer, Arnon Blum, Michael A. Bellio, Ivonne Hernandez Schulman, Barry E. Hurwitz, Meela Parker, Christopher R. Dermarkarian, Darcy L. DiFede, Wayne Balkan, Aisha Khan, Joshua M. Hare

Research output: Contribution to journalArticle

Abstract

Background: Endothelial dysfunction, characterized by diminished endothelial progenitor cell (EPC) function and flow-mediated vasodilation (FMD), is a clinically significant feature of heart failure (HF). Mesenchymal stem cells (MSCs), which have pro-angiogenic properties, have the potential to restore endothelial function. Accordingly, we tested the hypothesis that MSCs increase EPC function and restore flow-mediated vasodilation (FMD). Methods: Idiopathic dilated and ischemic cardiomyopathy patients were randomly assigned to receive autologous (n = 7) or allogeneic (n = 15) MSCs. We assessed EPC-colony forming units (EPC-CFUs), FMD, and circulating levels of vascular endothelial growth factor (VEGF) in patients before and three months after MSC transendocardial injection (n = 22) and in healthy controls (n = 10). Findings: EPC-colony forming units (CFUs) were markedly reduced in HF compared to healthy controls (4 ± 3 vs. 25 ± 16 CFUs, P <0.0001). Similarly, FMD% was impaired in HF (5.6 ± 3.2% vs 9.0 ± 3.3%, P = 0.01). Allogeneic, but not autologous, MSCs improved endothelial function three months after treatment (δ10 ± 5 vs δ1 ± 3 CFUs, P = 0.0067; δ3.7 ± 3% vs. δ-0.46 ± 3% FMD, P = 0.005). Patients who received allogeneic MSCs had a reduction in serum VEGF levels three months after treatment, while patients who received autologous MSCs had an increase (P = 0.0012), and these changes correlated with the change in EPC-CFUs (P <0.0001). Lastly, human umbilical vein endothelial cells (HUVECs) with impaired vasculogenesis due to pharmacologic nitric oxide synthase inhibition, were rescued by allogeneic MSC conditioned medium (P = 0.006). Interpretation: These findings reveal a novel mechanism whereby allogeneic, but not autologous, MSC administration results in the proliferation of functional EPCs and improvement in vascular reactivity, which in turn restores endothelial function towards normal in patients with HF. These findings have significant clinical and biological implications for the use of MSCs in HF and other disorders associated with endothelial dysfunction.

Original languageEnglish (US)
Pages (from-to)467-475
Number of pages9
JournalEBioMedicine
Volume2
Issue number5
DOIs
StatePublished - May 1 2015
Externally publishedYes

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Endothelial cells
Stem cells
Mesenchymal Stromal Cells
Heart Failure
Vasodilation
Stem Cells
Vascular Endothelial Growth Factor A
Endothelial Progenitor Cells
Patient treatment
Human Umbilical Vein Endothelial Cells
Dilated Cardiomyopathy
Conditioned Culture Medium
Nitric Oxide Synthase
Blood Vessels
Injections

Keywords

  • Autografts
  • Nitric oxide
  • Regenerative medicine
  • Vascular endothelium-dependent relaxation
  • Vasculogenesis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Premer, C., Blum, A., Bellio, M. A., Schulman, I. H., Hurwitz, B. E., Parker, M., ... Hare, J. M. (2015). Allogeneic Mesenchymal Stem Cells Restore Endothelial Function in Heart Failure by Stimulating Endothelial Progenitor Cells. EBioMedicine, 2(5), 467-475. https://doi.org/10.1016/j.ebiom.2015.03.020

Allogeneic Mesenchymal Stem Cells Restore Endothelial Function in Heart Failure by Stimulating Endothelial Progenitor Cells. / Premer, Courtney; Blum, Arnon; Bellio, Michael A.; Schulman, Ivonne Hernandez; Hurwitz, Barry E.; Parker, Meela; Dermarkarian, Christopher R.; DiFede, Darcy L.; Balkan, Wayne; Khan, Aisha; Hare, Joshua M.

In: EBioMedicine, Vol. 2, No. 5, 01.05.2015, p. 467-475.

Research output: Contribution to journalArticle

Premer, C, Blum, A, Bellio, MA, Schulman, IH, Hurwitz, BE, Parker, M, Dermarkarian, CR, DiFede, DL, Balkan, W, Khan, A & Hare, JM 2015, 'Allogeneic Mesenchymal Stem Cells Restore Endothelial Function in Heart Failure by Stimulating Endothelial Progenitor Cells', EBioMedicine, vol. 2, no. 5, pp. 467-475. https://doi.org/10.1016/j.ebiom.2015.03.020
Premer, Courtney ; Blum, Arnon ; Bellio, Michael A. ; Schulman, Ivonne Hernandez ; Hurwitz, Barry E. ; Parker, Meela ; Dermarkarian, Christopher R. ; DiFede, Darcy L. ; Balkan, Wayne ; Khan, Aisha ; Hare, Joshua M. / Allogeneic Mesenchymal Stem Cells Restore Endothelial Function in Heart Failure by Stimulating Endothelial Progenitor Cells. In: EBioMedicine. 2015 ; Vol. 2, No. 5. pp. 467-475.
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author = "Courtney Premer and Arnon Blum and Bellio, {Michael A.} and Schulman, {Ivonne Hernandez} and Hurwitz, {Barry E.} and Meela Parker and Dermarkarian, {Christopher R.} and DiFede, {Darcy L.} and Wayne Balkan and Aisha Khan and Hare, {Joshua M.}",
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AU - Premer, Courtney

AU - Blum, Arnon

AU - Bellio, Michael A.

AU - Schulman, Ivonne Hernandez

AU - Hurwitz, Barry E.

AU - Parker, Meela

AU - Dermarkarian, Christopher R.

AU - DiFede, Darcy L.

AU - Balkan, Wayne

AU - Khan, Aisha

AU - Hare, Joshua M.

PY - 2015/5/1

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N2 - Background: Endothelial dysfunction, characterized by diminished endothelial progenitor cell (EPC) function and flow-mediated vasodilation (FMD), is a clinically significant feature of heart failure (HF). Mesenchymal stem cells (MSCs), which have pro-angiogenic properties, have the potential to restore endothelial function. Accordingly, we tested the hypothesis that MSCs increase EPC function and restore flow-mediated vasodilation (FMD). Methods: Idiopathic dilated and ischemic cardiomyopathy patients were randomly assigned to receive autologous (n = 7) or allogeneic (n = 15) MSCs. We assessed EPC-colony forming units (EPC-CFUs), FMD, and circulating levels of vascular endothelial growth factor (VEGF) in patients before and three months after MSC transendocardial injection (n = 22) and in healthy controls (n = 10). Findings: EPC-colony forming units (CFUs) were markedly reduced in HF compared to healthy controls (4 ± 3 vs. 25 ± 16 CFUs, P <0.0001). Similarly, FMD% was impaired in HF (5.6 ± 3.2% vs 9.0 ± 3.3%, P = 0.01). Allogeneic, but not autologous, MSCs improved endothelial function three months after treatment (δ10 ± 5 vs δ1 ± 3 CFUs, P = 0.0067; δ3.7 ± 3% vs. δ-0.46 ± 3% FMD, P = 0.005). Patients who received allogeneic MSCs had a reduction in serum VEGF levels three months after treatment, while patients who received autologous MSCs had an increase (P = 0.0012), and these changes correlated with the change in EPC-CFUs (P <0.0001). Lastly, human umbilical vein endothelial cells (HUVECs) with impaired vasculogenesis due to pharmacologic nitric oxide synthase inhibition, were rescued by allogeneic MSC conditioned medium (P = 0.006). Interpretation: These findings reveal a novel mechanism whereby allogeneic, but not autologous, MSC administration results in the proliferation of functional EPCs and improvement in vascular reactivity, which in turn restores endothelial function towards normal in patients with HF. These findings have significant clinical and biological implications for the use of MSCs in HF and other disorders associated with endothelial dysfunction.

AB - Background: Endothelial dysfunction, characterized by diminished endothelial progenitor cell (EPC) function and flow-mediated vasodilation (FMD), is a clinically significant feature of heart failure (HF). Mesenchymal stem cells (MSCs), which have pro-angiogenic properties, have the potential to restore endothelial function. Accordingly, we tested the hypothesis that MSCs increase EPC function and restore flow-mediated vasodilation (FMD). Methods: Idiopathic dilated and ischemic cardiomyopathy patients were randomly assigned to receive autologous (n = 7) or allogeneic (n = 15) MSCs. We assessed EPC-colony forming units (EPC-CFUs), FMD, and circulating levels of vascular endothelial growth factor (VEGF) in patients before and three months after MSC transendocardial injection (n = 22) and in healthy controls (n = 10). Findings: EPC-colony forming units (CFUs) were markedly reduced in HF compared to healthy controls (4 ± 3 vs. 25 ± 16 CFUs, P <0.0001). Similarly, FMD% was impaired in HF (5.6 ± 3.2% vs 9.0 ± 3.3%, P = 0.01). Allogeneic, but not autologous, MSCs improved endothelial function three months after treatment (δ10 ± 5 vs δ1 ± 3 CFUs, P = 0.0067; δ3.7 ± 3% vs. δ-0.46 ± 3% FMD, P = 0.005). Patients who received allogeneic MSCs had a reduction in serum VEGF levels three months after treatment, while patients who received autologous MSCs had an increase (P = 0.0012), and these changes correlated with the change in EPC-CFUs (P <0.0001). Lastly, human umbilical vein endothelial cells (HUVECs) with impaired vasculogenesis due to pharmacologic nitric oxide synthase inhibition, were rescued by allogeneic MSC conditioned medium (P = 0.006). Interpretation: These findings reveal a novel mechanism whereby allogeneic, but not autologous, MSC administration results in the proliferation of functional EPCs and improvement in vascular reactivity, which in turn restores endothelial function towards normal in patients with HF. These findings have significant clinical and biological implications for the use of MSCs in HF and other disorders associated with endothelial dysfunction.

KW - Autografts

KW - Nitric oxide

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KW - Vascular endothelium-dependent relaxation

KW - Vasculogenesis

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