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Pre-Epicardial Cells Generated from Stem Cells Expected to Improve Engineered Heart Tissue

Key findings

  • Researchers at Massachusetts General Hospital have devised a high-efficiency method of generating pre-epicardial cells (PECs) from human induced pluripotent stem cells
  • As in normal embryonic development, the PECs developed into epicardial cells, which are key to ventricular wall formation
  • Co-culture of PECs and cardiomyocytes resulted in an aggregate of beating protoplasm with three-fold greater contractility than cardiomyocytes alone
  • Three-dimensional spheroid co-culture of PECs and cardiomyocytes generated electrically active cardiac microtissue with distinct luminal structures
  • These results suggest PECs can be used to create more sophisticated and mature cardiac grafts, with the ultimate goal of bioengineering heart tissue that can be transplanted for treatment of heart failure

Over the past decade, a breakthrough in cardiology research came when scientists learned how to differentiate human induced pluripotent stem cells (iPSCs) into contracting cardiomyocytes in vitro. Those cells may have applications in myocardial tissue engineering for regenerative medicine, cardiac cellular therapy and screening prospective medications for heart failure.

iPSCs are readily available—they are adult somatic cells that are reprogrammed to act like embryonic stem cells. The problem is that iPSC-derived cardiomyocytes remain underdeveloped and functionally immature. Therefore, the heart tissue bioengineered from such cells lacks the cellular and structural complexity of the native myocardium.

Now, researchers at Massachusetts General Hospital have devised a high-efficiency method of generating pre-epicardial cells (PECs), which can mature. The PECs developed into epicardial cells, which are key to ventricular wall formation in normal embryonic heart development.

Harald Ott, MD, thoracic surgeon, and Jun Jie Tan, DPhil, of the Center for Regenerative Medicine at Massachusetts General Hospital, and colleagues report the exciting advance in Nature Communications.

Two-Dimensional Culture

In well-insert experiments, PECs migrated toward cardiomyocytes and consolidated them into a more confined area. Direct co-culture of PECs with cardiomyocytes consolidated cardiomyocytes into dense aggregates.

The aggregates formed a beating protoplasm that demonstrated nearly three times more contractility than cardiomyocytes alone. Moreover, PECs stimulated cardiomyocyte proliferation, partly by secreting insulin-like growth factor 2. That hormone is essential to the ventricular cardiomyocyte proliferation that endogenous PECs induce during early heart development.

Three-Dimensional Culture

The researchers created a simplified in vitro model of three-dimensional heart tissue where they co-cultured cardiomyocytes spheres and PEC spheres. After 15 days they observed electrically active cardiac microtissue constructs with distinct internal luminal structures. Cardiomyocyte spheres cultured alone had only cystic structures.

Toward the Future

This work provides a foundation for incorporating PECs into the creation of more sophisticated and mature cardiac grafts. The ultimate goal is to use patients' cells to generate functioning heart tissue that could be transplanted for the treatment of heart failure.

Learn more about Dr. Ott's Research

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