Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation

Konstantinos E. Hatzistergos, Henry Quevedo, Behzad N. Oskouei, Qinghua Hu, Gary S. Feigenbaum, Irene S. Margitich, Ramesh Mazhari, Andrew J. Boyle, Juan P. Zambrano, Jose E. Rodriguez, Raul Dulce, Pradip Pattany, David Valdes, Concepcion Revilla, Alan W. Heldman, Ian McNiece, Joshua Hare

Research output: Contribution to journalArticle

505 Citations (Scopus)

Abstract

Rationale: The regenerative potential of the heart is insufficient to fully restore functioning myocardium after injury, motivating the quest for a cell-based replacement strategy. Bone marrow-derived mesenchymal stem cells (MSCs) have the capacity for cardiac repair that appears to exceed their capacity for differentiation into cardiac myocytes. Objective: Here, we test the hypothesis that bone marrow derived MSCs stimulate the proliferation and differentiation of endogenous cardiac stem cells (CSCs) as part of their regenerative repertoire. Methods And Results: Female Yorkshire pigs (n=31) underwent experimental myocardial infarction (MI), and 3 days later, received transendocardial injections of allogeneic male bone marrow-derived MSCs, MSC concentrated conditioned medium (CCM), or placebo (Plasmalyte). A no-injection control group was also studied. MSCs engrafted and differentiated into cardiomyocytes and vascular structures. In addition, endogenous c-kit + CSCs increased 20-fold in MSC-treated animals versus controls (P<0.001), there was a 6-fold increase in GATA-4+ CSCs in MSC versus control (P<0.001), and mitotic myocytes increased 4-fold (P=0.005). Porcine endomyocardial biopsies were harvested and plated as organotypic cultures in the presence or absence of MSC feeder layers. In vitro, MSCs stimulated c-kit+ CSCs proliferation into enriched populations of adult cardioblasts that expressed Nkx2-5 and troponin I. Conclusions: MSCs stimulate host CSCs, a new mechanism of action underlying successful cell-based therapeutics.

Original languageEnglish
Pages (from-to)913-922
Number of pages10
JournalCirculation Research
Volume107
Issue number7
DOIs
StatePublished - Oct 1 2010

Fingerprint

Mesenchymal Stromal Cells
Cell Differentiation
Stem Cells
Bone Marrow
Cell Proliferation
Cardiac Myocytes
Swine
Feeder Cells
Injections
Troponin I
Conditioned Culture Medium
Muscle Cells
Blood Vessels
Myocardium
Myocardial Infarction
Placebos
Biopsy
Control Groups
Wounds and Injuries

Keywords

  • cardiac stem cells
  • mesenchymal stem cells
  • myocardial infarction
  • myocardial regeneration

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Hatzistergos, K. E., Quevedo, H., Oskouei, B. N., Hu, Q., Feigenbaum, G. S., Margitich, I. S., ... Hare, J. (2010). Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation Research, 107(7), 913-922. https://doi.org/10.1161/CIRCRESAHA.110.222703

Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. / Hatzistergos, Konstantinos E.; Quevedo, Henry; Oskouei, Behzad N.; Hu, Qinghua; Feigenbaum, Gary S.; Margitich, Irene S.; Mazhari, Ramesh; Boyle, Andrew J.; Zambrano, Juan P.; Rodriguez, Jose E.; Dulce, Raul; Pattany, Pradip; Valdes, David; Revilla, Concepcion; Heldman, Alan W.; McNiece, Ian; Hare, Joshua.

In: Circulation Research, Vol. 107, No. 7, 01.10.2010, p. 913-922.

Research output: Contribution to journalArticle

Hatzistergos, KE, Quevedo, H, Oskouei, BN, Hu, Q, Feigenbaum, GS, Margitich, IS, Mazhari, R, Boyle, AJ, Zambrano, JP, Rodriguez, JE, Dulce, R, Pattany, P, Valdes, D, Revilla, C, Heldman, AW, McNiece, I & Hare, J 2010, 'Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation', Circulation Research, vol. 107, no. 7, pp. 913-922. https://doi.org/10.1161/CIRCRESAHA.110.222703
Hatzistergos KE, Quevedo H, Oskouei BN, Hu Q, Feigenbaum GS, Margitich IS et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circulation Research. 2010 Oct 1;107(7):913-922. https://doi.org/10.1161/CIRCRESAHA.110.222703
Hatzistergos, Konstantinos E. ; Quevedo, Henry ; Oskouei, Behzad N. ; Hu, Qinghua ; Feigenbaum, Gary S. ; Margitich, Irene S. ; Mazhari, Ramesh ; Boyle, Andrew J. ; Zambrano, Juan P. ; Rodriguez, Jose E. ; Dulce, Raul ; Pattany, Pradip ; Valdes, David ; Revilla, Concepcion ; Heldman, Alan W. ; McNiece, Ian ; Hare, Joshua. / Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. In: Circulation Research. 2010 ; Vol. 107, No. 7. pp. 913-922.
@article{02196de969384233b214a2ba0b4eb1a9,
title = "Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation",
abstract = "Rationale: The regenerative potential of the heart is insufficient to fully restore functioning myocardium after injury, motivating the quest for a cell-based replacement strategy. Bone marrow-derived mesenchymal stem cells (MSCs) have the capacity for cardiac repair that appears to exceed their capacity for differentiation into cardiac myocytes. Objective: Here, we test the hypothesis that bone marrow derived MSCs stimulate the proliferation and differentiation of endogenous cardiac stem cells (CSCs) as part of their regenerative repertoire. Methods And Results: Female Yorkshire pigs (n=31) underwent experimental myocardial infarction (MI), and 3 days later, received transendocardial injections of allogeneic male bone marrow-derived MSCs, MSC concentrated conditioned medium (CCM), or placebo (Plasmalyte). A no-injection control group was also studied. MSCs engrafted and differentiated into cardiomyocytes and vascular structures. In addition, endogenous c-kit + CSCs increased 20-fold in MSC-treated animals versus controls (P<0.001), there was a 6-fold increase in GATA-4+ CSCs in MSC versus control (P<0.001), and mitotic myocytes increased 4-fold (P=0.005). Porcine endomyocardial biopsies were harvested and plated as organotypic cultures in the presence or absence of MSC feeder layers. In vitro, MSCs stimulated c-kit+ CSCs proliferation into enriched populations of adult cardioblasts that expressed Nkx2-5 and troponin I. Conclusions: MSCs stimulate host CSCs, a new mechanism of action underlying successful cell-based therapeutics.",
keywords = "cardiac stem cells, mesenchymal stem cells, myocardial infarction, myocardial regeneration",
author = "Hatzistergos, {Konstantinos E.} and Henry Quevedo and Oskouei, {Behzad N.} and Qinghua Hu and Feigenbaum, {Gary S.} and Margitich, {Irene S.} and Ramesh Mazhari and Boyle, {Andrew J.} and Zambrano, {Juan P.} and Rodriguez, {Jose E.} and Raul Dulce and Pradip Pattany and David Valdes and Concepcion Revilla and Heldman, {Alan W.} and Ian McNiece and Joshua Hare",
year = "2010",
month = "10",
day = "1",
doi = "10.1161/CIRCRESAHA.110.222703",
language = "English",
volume = "107",
pages = "913--922",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "7",

}

TY - JOUR

T1 - Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation

AU - Hatzistergos, Konstantinos E.

AU - Quevedo, Henry

AU - Oskouei, Behzad N.

AU - Hu, Qinghua

AU - Feigenbaum, Gary S.

AU - Margitich, Irene S.

AU - Mazhari, Ramesh

AU - Boyle, Andrew J.

AU - Zambrano, Juan P.

AU - Rodriguez, Jose E.

AU - Dulce, Raul

AU - Pattany, Pradip

AU - Valdes, David

AU - Revilla, Concepcion

AU - Heldman, Alan W.

AU - McNiece, Ian

AU - Hare, Joshua

PY - 2010/10/1

Y1 - 2010/10/1

N2 - Rationale: The regenerative potential of the heart is insufficient to fully restore functioning myocardium after injury, motivating the quest for a cell-based replacement strategy. Bone marrow-derived mesenchymal stem cells (MSCs) have the capacity for cardiac repair that appears to exceed their capacity for differentiation into cardiac myocytes. Objective: Here, we test the hypothesis that bone marrow derived MSCs stimulate the proliferation and differentiation of endogenous cardiac stem cells (CSCs) as part of their regenerative repertoire. Methods And Results: Female Yorkshire pigs (n=31) underwent experimental myocardial infarction (MI), and 3 days later, received transendocardial injections of allogeneic male bone marrow-derived MSCs, MSC concentrated conditioned medium (CCM), or placebo (Plasmalyte). A no-injection control group was also studied. MSCs engrafted and differentiated into cardiomyocytes and vascular structures. In addition, endogenous c-kit + CSCs increased 20-fold in MSC-treated animals versus controls (P<0.001), there was a 6-fold increase in GATA-4+ CSCs in MSC versus control (P<0.001), and mitotic myocytes increased 4-fold (P=0.005). Porcine endomyocardial biopsies were harvested and plated as organotypic cultures in the presence or absence of MSC feeder layers. In vitro, MSCs stimulated c-kit+ CSCs proliferation into enriched populations of adult cardioblasts that expressed Nkx2-5 and troponin I. Conclusions: MSCs stimulate host CSCs, a new mechanism of action underlying successful cell-based therapeutics.

AB - Rationale: The regenerative potential of the heart is insufficient to fully restore functioning myocardium after injury, motivating the quest for a cell-based replacement strategy. Bone marrow-derived mesenchymal stem cells (MSCs) have the capacity for cardiac repair that appears to exceed their capacity for differentiation into cardiac myocytes. Objective: Here, we test the hypothesis that bone marrow derived MSCs stimulate the proliferation and differentiation of endogenous cardiac stem cells (CSCs) as part of their regenerative repertoire. Methods And Results: Female Yorkshire pigs (n=31) underwent experimental myocardial infarction (MI), and 3 days later, received transendocardial injections of allogeneic male bone marrow-derived MSCs, MSC concentrated conditioned medium (CCM), or placebo (Plasmalyte). A no-injection control group was also studied. MSCs engrafted and differentiated into cardiomyocytes and vascular structures. In addition, endogenous c-kit + CSCs increased 20-fold in MSC-treated animals versus controls (P<0.001), there was a 6-fold increase in GATA-4+ CSCs in MSC versus control (P<0.001), and mitotic myocytes increased 4-fold (P=0.005). Porcine endomyocardial biopsies were harvested and plated as organotypic cultures in the presence or absence of MSC feeder layers. In vitro, MSCs stimulated c-kit+ CSCs proliferation into enriched populations of adult cardioblasts that expressed Nkx2-5 and troponin I. Conclusions: MSCs stimulate host CSCs, a new mechanism of action underlying successful cell-based therapeutics.

KW - cardiac stem cells

KW - mesenchymal stem cells

KW - myocardial infarction

KW - myocardial regeneration

UR - http://www.scopus.com/inward/record.url?scp=77958012860&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77958012860&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.110.222703

DO - 10.1161/CIRCRESAHA.110.222703

M3 - Article

C2 - 20671238

AN - SCOPUS:77958012860

VL - 107

SP - 913

EP - 922

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 7

ER -