Biomedical Engineering Reference
In-Depth Information
Reprogramming of Fibroblasts into Functional Cardiomyocytes
The reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs) raises
the possibility that a somatic cell could be reprogrammed to an alternative differen-
tiated fate without first becoming a stem/progenitor cell. A large pool of fibroblasts
exists in the postnatal heart, yet no single “master regulator” of direct cardiac repro-
gramming has been identified. A combination of three developmental transcription
factors (Gata4, Mef2c, and Tbx5) have been shown to rapidly and efficiently repro-
gram postnatal cardiac or dermal fibroblasts directly into differentiated cardiomyocyte-
like cells (Ieda et al.
2010
). Such induced cardiomyocytes express cardiac-specific
biomarkers, have a global gene expression profile similar to cardiomyocytes, and
contract spontaneously. Fibroblasts transplanted into mouse hearts 1 day after
transduction of the three factors also differentiated into cardiomyocyte-like cells.
These findings demonstrate that functional cardiomyocytes can be directly repro-
grammed from differentiated somatic cells by defined factors. Reprogramming of
endogenous or transplanted fibroblasts might provide a source of cardiomyocytes
for regenerative approaches to the damaged heart. Much work remains to be done
before these findings can be translated into clinical use. Some of the issues that
need to be resolved are (Murry and Pu
2011
):
•
The efficiency of generating functioning cardiomyocytes requires improvement
as only ~1% of reprogrammed myocytes appeared to be bona fide beating
cardiomyocytes.
Reprogramming systems should be developed without use of integrating
•
viruses.
There is need to determine if the induced cardiomyocyte state persists over the
•
long term. The investigators should demonstrate that these cells can integrate
into the injured heart, beat synchronously with the host myocardium, and restore
electrical and contractile function.
Small Molecules to Enhance Myocardial Repair by Stem Cells
The clinical success of stem cell therapy for myocardial repair hinges on a better
understanding of cardiac fate mechanisms. Small molecules involved in cardiac fate
have been identified by screening a chemical library for activators of the signature
gene Nkx2.5, using a luciferase knockin bacterial artificial chromosome in
mouse P19CL6 pluripotent stem cells (Sadek et al.
2008
). A family of sulfonyl-
hydrazone (Shz) small molecules, particularly, Shz-3 has been shown to trigger
cardiac mRNA and protein expression in a variety of embryonic and adult stem/
progenitor cells, including human mobilized peripheral blood mononuclear cells
(M-PBMCs) when cultured for 3 days, and then for 7 days without the drug. Small-
molecule-enhanced M-PBMCs engrafted into the rat heart in proximity to an
experimental injury improved cardiac function better than control cells. Recovery of
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