TY - JOUR
T1 - Brachyury engineers cardiac repair competent stem cells
AU - Li, Mark
AU - Yamada, Satsuki
AU - Shi, Ao
AU - Singh, Raman Deep
AU - Rolland, Tyler J.
AU - Jeon, Ryounghoon
AU - Lopez, Natalia
AU - Shelerud, Lukas
AU - Terzic, Andre
AU - Behfar, Atta
N1 - Funding Information:
The authors thank Lois A. Rowe for histopathology, Katrina M. Tollefsrud for echocardiography analysis, and Dr Yue Yu for RNA informatics. Christopher Livia assisted with IncuCyte and immunohistochemistry, Timothy E. Peterson with antioxidant assay, Yue Wu with macrophage polarization, Sinibaldo R. Romero Arocha with Brachyury transfection, and Tyra A. Witt and Mary E. Nagel with in vivo tests. The authors acknowledge NIH (R01 HL134664; T32 HL07111), Regenerative Medicine Minnesota (021218BT001), the Van Cleve Cardiac Regenerative Medicine Program, Marriott Family Foundation, A. Gary and Anita Klesch Predoctoral Fellowship, Mayo Bonner MD‐PhD Scholarship, Michael S. and Mary Sue Shannon Family, and Mayo Clinic Center for Regenerative Medicine.
Funding Information:
S.Y., A.T., and A.B. are coinventors on regenerative sciences related intellectual property disclosed to Mayo Clinic. Previously, Mayo Clinic has administered research grants from Celyad. Mayo Clinic, A.T. and A.B. have interests in Rion LLC.
Funding Information:
Mayo Clinic Center for Regenerative Medicine; Michael S. and Mary Sue Shannon Family; Mayo Bonner MD‐PhD Scholarship; A. Gary and Anita Klesch Predoctoral Fellowship; Marriott Family Foundation; Van Cleve Cardiac Regenerative Medicine Program; Regenerative Medicine Minnesota, Grant/Award Number: 021218BT001; NIH, Grant/Award Numbers: T32 HL07111, R01 HL134664 Funding information
Publisher Copyright:
© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals LLC on behalf of AlphaMed Press.
PY - 2021/3
Y1 - 2021/3
N2 - To optimize the regenerative proficiency of stem cells, a cardiopoietic protein-based cocktail consisting of multiple growth factors has been developed and advanced into clinical trials for treatment of ischemic heart failure. Streamlining the inductors of cardiopoiesis would address the resource intensive nature of the current stem cell enhancement protocol. To this end, the microencapsulated-modified-mRNA (M3RNA) technique was here applied to introduce early cardiogenic genes into human adipose-derived mesenchymal stem cells (AMSCs). A single mesodermal transcription factor, Brachyury, was sufficient to trigger high expression of cardiopoietic markers, Nkx2.5 and Mef2c. Engineered cardiopoietic stem cells (eCP) featured a transcriptome profile distinct from pre-engineered AMSCs. In vitro, eCP demonstrated protective antioxidant capacity with enhanced superoxide dismutase expression and activity; a vasculogenic secretome driving angiogenic tube formation; and macrophage polarizing immunomodulatory properties. In vivo, in a murine model of myocardial infarction, intramyocardial delivery of eCP (600 000 cells per heart) improved cardiac performance and protected against decompensated heart failure. Thus, heart repair competent stem cells, armed with antioxidant, vasculogenic, and immunomodulatory traits, are here engineered through a protein-independent single gene manipulation, expanding the available regenerative toolkit.
AB - To optimize the regenerative proficiency of stem cells, a cardiopoietic protein-based cocktail consisting of multiple growth factors has been developed and advanced into clinical trials for treatment of ischemic heart failure. Streamlining the inductors of cardiopoiesis would address the resource intensive nature of the current stem cell enhancement protocol. To this end, the microencapsulated-modified-mRNA (M3RNA) technique was here applied to introduce early cardiogenic genes into human adipose-derived mesenchymal stem cells (AMSCs). A single mesodermal transcription factor, Brachyury, was sufficient to trigger high expression of cardiopoietic markers, Nkx2.5 and Mef2c. Engineered cardiopoietic stem cells (eCP) featured a transcriptome profile distinct from pre-engineered AMSCs. In vitro, eCP demonstrated protective antioxidant capacity with enhanced superoxide dismutase expression and activity; a vasculogenic secretome driving angiogenic tube formation; and macrophage polarizing immunomodulatory properties. In vivo, in a murine model of myocardial infarction, intramyocardial delivery of eCP (600 000 cells per heart) improved cardiac performance and protected against decompensated heart failure. Thus, heart repair competent stem cells, armed with antioxidant, vasculogenic, and immunomodulatory traits, are here engineered through a protein-independent single gene manipulation, expanding the available regenerative toolkit.
KW - RNA engineering
KW - cardiopoiesis
KW - cardiopoietic stem cells
KW - heart failure
KW - myocardial infarction
KW - regenerative therapy
UR - http://www.scopus.com/inward/record.url?scp=85093985672&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85093985672&partnerID=8YFLogxK
U2 - 10.1002/sctm.20-0193
DO - 10.1002/sctm.20-0193
M3 - Article
C2 - 33098750
AN - SCOPUS:85093985672
VL - 10
SP - 385
EP - 397
JO - Stem cells translational medicine
JF - Stem cells translational medicine
SN - 2157-6564
IS - 3
ER -