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Patching Up the Heart – iPSC-Derived cardiomyocytes do the job!

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Review of “Functional Effects of a Tissue-Engineered Cardiac Patch from Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in a Rat Infarct Model” from Stem Cells Translational Medicine by Stuart P. Atkinson

Patching up a broken heart sounds like a job for a grief counselor and not a stem cell scientist, but even so, great advances have been made in the creation of engineered cardiac tissues to repair the heart. Application as a patch provides multiple advantages over direct injection of cells into the myocardium, and the laboratory of Robert T. Tranquillo (University of Minnesota, USA) sought to assess whether human induced pluripotent stem cells (hiPSCs) were an adequate source for the cardiomyocytes (CMs) required as one element in an effective patch. In their new study, published in Stem Cells Translational Medicine, they show that when contained within such a patch, hiPSCs-CMs survive, proliferate, and enhance heart regeneration in a rat model [1].

To create patches for implantation onto the rat heart, the researchers combined the hiPSC-CMs with human pericytes, a vascular support cell, within a fibrin gel. A small molecule Wnt/GSK3 inhibition protocol [2] combined with lactate-based metabolomic purification [3] produced the hiPSCs-CMs, and the added pericytes mediated the proper alignment of the CMs (required for proper beating) [4] and supported microvessel growth into the patch [28]. Encouragingly, the compacted patch generated a measurable force in response multiple pacing frequencies in vitro (or in short, it had the ability to beat!)), and, following implantation onto the infarcted rat heart, the hiPSC-CMs within the patches survived and even proliferated.

This all combined to mediate obvious improvements in heart function, which included a reduction in infarct size (see figure) and greater fractional shortening at 4 weeks post surgery. However, fractional shortening declined after 4 weeks and some left ventricular wall thinning still occurred. These improvements correlated to the vascularization of the patch, with an increase in the number of microvessels appearing at the host-patch interface suggesting that a potent paracrine mechanism underlies the reduction in the infarct and the short-term functional improvements observed.

The authors believe this to be the first hiPSC-CM-containing patch which can survive long term and promote regeneration of the heart following a heart attack-induced damage. While this and another related study [5] do show some obvious benefits of patch-mediated CM administration, the patch still needs some “tweaking” in order to further improve myocardial recovery. Furthermore, the group wants to extend their work to study an autologous source for pericytes, longer-term graft survival, teratoma formation, and the effects of the patch in a large animal study.

References

  1. Wendel JS, Ye L, Tao R, et al. Functional Effects of a Tissue-Engineered Cardiac Patch From Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in a Rat Infarct Model. Stem Cells Transl Med 2015;4:1324-1332.
  2. Lian X, Zhang J, Azarin SM, et al. Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/beta-catenin signaling under fully defined conditions. Nat Protoc 2013;8:162-175.
  3. Tohyama S, Hattori F, Sano M, et al. Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell 2013;12:127-137.
  4. Wendel JS, Ye L, Zhang P, et al. Functional consequences of a tissue-engineered myocardial patch for cardiac repair in a rat infarct model. Tissue Eng Part A 2014;20:1325-1335.
  5. Masumoto H, Ikuno T, Takeda M, et al. Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration. Sci Rep 2014;4:6716.