C-kit + precursors support postinfarction myogenesis in the neonatal, but not adult, heart

Sophy A. Jesty, Michele A Steffey, Frank K. Lee, Martin Breitbach, Michael Hesse, Shaun Reining, Jane C. Lee, Robert M. Doran, Alexander Yu Nikitin, Bernd K. Fleischmann, Michael I. Kotlikoff

Research output: Contribution to journalArticle

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Abstract

We examined the myogenic response to infarction in neonatal and adult mice to determine the role of c-kit + cardiovascular precursor cells (CPC) that are known to be present in early heart development. Infarction of postnatal day 1-3 c-kit BAC-EGFP mouse hearts induced the localized expansion of (c-kit)EGFP + cells within the infarct, expression of the c-kit and Nkx2.5 mRNA, myogenesis, and partial regeneration of the infarction, with (c-kit)EGFP+ cells adopting myogenic and vascular fates. Conversely, infarction of adult mice resulted in a modest induction of (c-kit)EGFP + cells within the infarct, which did not express Nkx2.5 or undergo myogenic differentiation, but adopted a vascular fate within the infarction, indicating a lack of authentic CPC. Explantation of infarcted neonatal and adult heart tissue to scid mice, and adoptive transfer of labeled bone marrow, confirmed the cardiac source of myogenic (neonate) and angiogenic (neonate and adult) cells. FACS-purified (c-kit)EGFP +/(αMHC)mCherry - (noncardiac) cells from microdissected infarcts within 6 h of infarction underwent cardiac differentiation, forming spontaneously beating myocytes in vitro; cre/LoxP fate mapping identified a noncardiac population of (c-kit)EGFP + myocytes within infarctions, indicating that the induction of undifferentiated precursors contributes to localized myogenesis. Thus, adult postinfarct myogenic failure is likely not due to a context-dependent restriction of precursor differentiation, and c-kit induction following injury of the adult heart does not define precursor status.

Original languageEnglish (US)
Pages (from-to)13380-13385
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number33
DOIs
StatePublished - Aug 14 2012

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Muscle Development
Infarction
Muscle Cells
Blood Vessels
Heart Injuries
Adoptive Transfer
Regeneration
Bone Marrow
Messenger RNA
Population

Keywords

  • Angiogenesis
  • Heart repair
  • Stem cell
  • Vasculogenesis

ASJC Scopus subject areas

  • General

Cite this

C-kit + precursors support postinfarction myogenesis in the neonatal, but not adult, heart. / Jesty, Sophy A.; Steffey, Michele A; Lee, Frank K.; Breitbach, Martin; Hesse, Michael; Reining, Shaun; Lee, Jane C.; Doran, Robert M.; Nikitin, Alexander Yu; Fleischmann, Bernd K.; Kotlikoff, Michael I.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 33, 14.08.2012, p. 13380-13385.

Research output: Contribution to journalArticle

Jesty, SA, Steffey, MA, Lee, FK, Breitbach, M, Hesse, M, Reining, S, Lee, JC, Doran, RM, Nikitin, AY, Fleischmann, BK & Kotlikoff, MI 2012, 'C-kit + precursors support postinfarction myogenesis in the neonatal, but not adult, heart', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 33, pp. 13380-13385. https://doi.org/10.1073/pnas.1208114109
Jesty, Sophy A. ; Steffey, Michele A ; Lee, Frank K. ; Breitbach, Martin ; Hesse, Michael ; Reining, Shaun ; Lee, Jane C. ; Doran, Robert M. ; Nikitin, Alexander Yu ; Fleischmann, Bernd K. ; Kotlikoff, Michael I. / C-kit + precursors support postinfarction myogenesis in the neonatal, but not adult, heart. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 33. pp. 13380-13385.
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AU - Steffey, Michele A

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AU - Breitbach, Martin

AU - Hesse, Michael

AU - Reining, Shaun

AU - Lee, Jane C.

AU - Doran, Robert M.

AU - Nikitin, Alexander Yu

AU - Fleischmann, Bernd K.

AU - Kotlikoff, Michael I.

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N2 - We examined the myogenic response to infarction in neonatal and adult mice to determine the role of c-kit + cardiovascular precursor cells (CPC) that are known to be present in early heart development. Infarction of postnatal day 1-3 c-kit BAC-EGFP mouse hearts induced the localized expansion of (c-kit)EGFP + cells within the infarct, expression of the c-kit and Nkx2.5 mRNA, myogenesis, and partial regeneration of the infarction, with (c-kit)EGFP+ cells adopting myogenic and vascular fates. Conversely, infarction of adult mice resulted in a modest induction of (c-kit)EGFP + cells within the infarct, which did not express Nkx2.5 or undergo myogenic differentiation, but adopted a vascular fate within the infarction, indicating a lack of authentic CPC. Explantation of infarcted neonatal and adult heart tissue to scid mice, and adoptive transfer of labeled bone marrow, confirmed the cardiac source of myogenic (neonate) and angiogenic (neonate and adult) cells. FACS-purified (c-kit)EGFP +/(αMHC)mCherry - (noncardiac) cells from microdissected infarcts within 6 h of infarction underwent cardiac differentiation, forming spontaneously beating myocytes in vitro; cre/LoxP fate mapping identified a noncardiac population of (c-kit)EGFP + myocytes within infarctions, indicating that the induction of undifferentiated precursors contributes to localized myogenesis. Thus, adult postinfarct myogenic failure is likely not due to a context-dependent restriction of precursor differentiation, and c-kit induction following injury of the adult heart does not define precursor status.

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