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Myocardial Infarction in Neonatal Mice, A Model of Cardiac Regeneration
Published on: May 24, 2016
c-kit+ precursors support postinfarction myogenesis in the neonatal, but not adult, heart
Sophy A Jesty1, Michele A Steffey, Frank K Lee
1Department of Biomedical Science, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Insights
Neonatal mice show c-kit(+) cell expansion and myogenesis after infarction, aiding heart regeneration. Adult mice lack this response, indicating adult c-kit(+) cells do not act as true cardiovascular precursor cells (CPC).
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Developmental Biology
Background:
- Cardiovascular precursor cells (CPC) expressing c-kit are crucial for early heart development.
- Understanding their role in adult heart regeneration after infarction is critical.
Purpose of the Study:
- To investigate the myogenic response to infarction in neonatal versus adult mice.
- To determine the role and fate of c-kit(+) cells post-myocardial infarction.
Main Methods:
- Infarction model in neonatal and adult c-kit(BAC)-EGFP mice.
- Analysis of cell expansion, gene expression (c-kit, Nkx2.5), and differentiation.
- Explantation, adoptive bone marrow transfer, and FACS purification.
- In vitro cardiac differentiation and cre/LoxP fate mapping.
Main Results:
- Neonatal infarction induced c-kit(+) cell expansion, myogenesis, and partial regeneration.
- Adult infarction showed limited c-kit(+) cell induction, primarily adopting vascular fates without myogenesis.
- Cardiac-derived c-kit(+) cells contributed to myogenesis in neonates, while adult cells contributed to angiogenesis.
- Isolated neonatal noncardiac c-kit(+) cells differentiated into beating myocytes in vitro.
Conclusions:
- Neonatal c-kit(+) cells contribute to cardiac regeneration via myogenesis.
- Adult c-kit(+) cells do not function as CPCs for myogenesis post-infarction.
- Adult post-infarct myogenic failure is not due to restricted precursor differentiation.
- Induced c-kit expression in adults does not signify precursor status.
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.
