An integrated statistical model for enhanced murine cardiomyocyte differentiation via optimized engagement of 3D extracellular matrices

Jangwook P. Jung, Dongjian Hu, Ibrahim J. Domian, Brenda M. Ogle

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39 Scopus citations


The extracellular matrix (ECM) impacts stem cell differentiation, but identifying formulations supportive of differentiation is challenging in 3D models. Prior efforts involving combinatorial ECM arrays seemed intuitively advantageous. We propose an alternative that suggests reducing sample size and technological burden can be beneficial and accessible when coupled to design of experiments approaches. We predict optimized ECM formulations could augment differentiation of cardiomyocytes derived in vitro. We employed native chemical ligation to polymerize 3D poly (ethylene glycol) hydrogels under mild conditions while entrapping various combinations of ECM and murine induced pluripotent stem cells. Systematic optimization for cardiomyocyte differentiation yielded a predicted solution of 61%, 24%, and 15% of collagen type I, laminin-111, and fibronectin, respectively. This solution was confirmed by increased numbers of cardiac troponin T, α-myosin heavy chain and α-sarcomeric actinin-expressing cells relative to suboptimum solutions. Cardiomyocytes of composites exhibited connexin43 expression, appropriate contractile kinetics and intracellular calcium handling. Further, adding a modulator of adhesion, thrombospondin-1, abrogated cardiomyocyte differentiation. Thus, the integrated biomaterial platform statistically identified an ECM formulation best supportive of cardiomyocyte differentiation. In future, this formulation could be coupled with biochemical stimulation to improve functional maturation of cardiomyocytes derived in vitro or transplanted in vivo.

Original languageEnglish (US)
Article number18705
JournalScientific reports
StatePublished - Dec 21 2015

Bibliographical note

Funding Information:
The authors thank Prof. Jonathan Marchant for helpful discussion on imaging Ca2+ transients and Prof. Deepak Srivastava for kindly providing miPSCs. The DIC and confocal imaging of Ca2+ transients was performed at the University Imaging Center of the University of Minnesota. Epifluorescence and MPLSM was performed in the Alford and the Provenzano lab, respectively. This work was supported by the National Science Foundation (1445650) and the American Heart Association Postdoctoral Fellowship (13POST14080011).


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