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Evolution of the c-kit-positive cell response to pathological challenge in the myocardium
Jenna Fransioli1, Brandi Bailey, Natalie A Gude
1Department of Biology, San Diego State University Heart Institute, San Diego State University, San Diego, California 92182, USA.
Insights
Stem cells expressing c-kit are recruited to the heart for repair after injury. Genetically engineered mice using green fluorescent protein (GFP) enabled clear identification of these crucial c-kit+ cells in myocardial regeneration.
Area of Science:
- Cardiovascular Biology
- Stem Cell Biology
- Regenerative Medicine
Background:
- The myocardium's response to injury involves stem and progenitor cells for repair.
- Identifying these recruited cells has been challenging due to a lack of specific markers, causing scientific debate.
Purpose of the Study:
- To unambiguously identify and track c-kit+ stem/progenitor cells in the myocardium.
- To investigate the role of these cells in cardiac repair following injury using a novel transgenic model.
Main Methods:
- Utilized a transgenic mouse model expressing green fluorescent protein (GFP) under the c-kit promoter.
- Quantified GFP and c-kit expression and cell accumulation in neonatal and adult mice.
- Analyzed cell populations post-myocardial infarction (MI) and in cardiac cell cultures.
Main Results:
- GFP expression under the c-kit promoter identified a specific subset of c-kit+ cells.
- GFP-positive cell numbers were highest at birth, declining by week 2, mirroring c-kit expression.
- Myocardial infarction increased GFP- and c-kit-positive cells in the injured area.
- Differentiated cardiac-resident c-kit+ cells showed diminished GFP expression.
Conclusions:
- Genetically engineered mice provide a reliable tool to study c-kit+ cells in cardiac repair.
- These findings validate the concept of c-kit+ cells actively participating in myocardial regeneration after injury.
Abstract:
Cumulative evidence indicates that myocardium responds to growth or injury by recruitment of stem and/or progenitor cells that participate in repair and regenerative processes. Unequivocal identification of this population has been hampered by lack of reagents or markers specific to the recruited population, leading to controversies regarding the nature of these cells. Use of a transgenic mouse expressing green fluorescent protein driven by the c-kit promoter allows for unambiguous identification of this cell population. Green fluorescent protein (GFP) driven by the c-kit promoter labels a fraction of the c-kit+ cells recognized by antibody labeling for c-kit protein. Expression of GFP by the c-kit promoter and accumulation of GFP-positive cells in the myocardium is relatively high at birth compared with adult and declines between postnatal weeks 1 and 2, which tracks in parallel with expression of c-kit protein and c-kit-positive cells. Acute cardiomyopathic injury by infarction prompts increased expression of both GFP protein and GFP-labeled cells in the region of infarction relative to remote myocardium. Similar increases were observed for c-kit protein and cells with a slightly earlier onset and decline relative to the GFP signal. Cells coexpressing GFP, c-kit, and cardiogenic markers were apparent at 1-2 weeks postinfarction. Cardiac-resident c-kit+ cell cultures derived from the transgenic line express GFP that is diminished in parallel with c-kit by induction of differentiation. The use of genetically engineered mice validates and extends the concept of c-kit+ cells participating in the response to myocardial injury.
