BRUNNER-DISSERTATION-2017.pdf (35.03 MB)
Loss of Additional Sex Combs Like 2 Leads to De Novo Cardiomyocyte Production in Adult Mice
thesis
posted on 2017-10-28, 00:00 authored by Rachel Lee BrunnerHeart disease is a top health concern globally, with heart attacks affecting more than seven million people worldwide each year. A heart attack results in the rapid death of heart muscle cells, known as cardiomyocytes. The adult heart does not effectively regenerate these lost cardiomyocytes. Instead, the healing process is primarily characterized by development of scar tissue. While scarring is crucial to the continuation of heart function in the short term, it leads to gradual deterioration of heart’s ability to adequately pump blood. Therefore, a significant research goal has been to replace lost cardiomyocytes to prevent heart failure. Towards this goal, we report that loss of the epigenetic regulator, ASXL2, results in increased de novo cardiomyocyte production in the adult mouse heart. The adult Asxl2-/- heart exhibits overgrowth. While the dominant mechanism for growth of the normal adult heart is by growth in size of existing cardiomyocytes, Asxl2-/- cardiomyocytes are not hypertrophic. Therefore, we asked if there was an increase in cardiomyocyte production in the Asxl2-/- heart. Proliferation assays reveal a 3- to 5-fold increase in proliferation of vimentin+ non-cardiomyocytes in the Asxl2-/- heart compared to wildtype controls. In contrast, the rate of cardiomyocyte proliferation is low and comparable for both genotypes. Interestingly, an increased fraction of proliferating non-cardiomyocytes in the Asxl2-/- heart express cardiogenic markers NKX2-5 and MEF2C. Approximately 10% of proliferating non-cardiomyocytes were NKX2-5+ in the Asxl2-/- heart, compared to only ~1.3% in the wildtype control. MEF2C+ non-cardiomyocytes represented ~50% of proliferating non-cardiomyocytes in the Asxl2-/-, compared to ~20% in the wildtype control. The fate of proliferating non-cardiomyocytes was followed by EdU pulse-chase lineage tracing. After a 4-week chase period, ~6% of EdU+ cells in the Asxl2-/- heart are cardiomyocytes, while EdU+ cardiomyocytes were not observed in the wildtype control. Isolated EdU+ cardiomyocytes from the Asxl2-/- heart display a range of phenotypes consistent with different stages of cardiomyocyte maturation. Taken together, these data indicate de novo cardiomyocyte production by a population of proliferative cardiogenic non-cardiomyocytes in the Asxl2-/- heart. The identification of ASXL2 as a potential epigenetic roadblock to cardiogenicity raises the intriguing possibility of using epigenetic therapies to induce cardiogenic differentiation of dormant non-cardiomyocyte progenitors.
History
Advisor
Okkema, PeterChair
Orenic, TeresaDepartment
Biological SciencesDegree Grantor
University of Illinois at ChicagoDegree Level
- Doctoral
Committee Member
Benevolenskaya, Elizaveta Conway, Simon Wang, Q. TianSubmitted date
May 2017Issue date
2017-03-29Usage metrics
Categories
No categories selectedLicence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC