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MHC-matched iPSCs: The Way Forward for Regenerative Medicine?

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Review of “Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts” from Nature by Stuart P. Atkinson

A wide range of human diseases and disorders may be treatable using strategies based on the application of immunocompatible and patient-specific induced pluripotent stem cells (iPSCs). However, creating iPSCs specific for each patient will entail huge labor and monetary costs, making the clinical translation of iPSC-based strategies on a patient-by-patient basis very difficult.

But is there another way forward for regenerative medicine? Researchers from the laboratory of Yuji Shiba (Shinshu University, Matsumoto, Japan) believe that the application of major histocompatibility complex (MHC)-matched iPSCs may represent a more feasible approach. Employing MHC-matched iPSCs will limit the level of the immune response [1, 2] so allowing the therapeutic application of one batch of cells to a multitude of genetically dissimilar patients under conditions of minimal immunosuppression.

In a new study published in Nature, Shiba et al now demonstrate that cardiomyocytes differentiated from MHC-matched iPSCs (iPSC-CMs) can survive long-term and regenerate heart muscle following transplantation in a non-human primate myocardial infarction model [3]. So do MHC-matched iPSCs represent the way forward for regenerative medicine?

The reprogramming process utilized plasmid-based overexpression of OCT4, SOX2, KLF4, and L-MYC (MYCL) in cynomolgus monkey skin fibroblasts to generate pluripotent and karyotypically stable iPSCs. Then, employing a modified protocol [4-6], the authors differentiated iPSCs into CMs displaying the required electrophysiological characteristics.

As expected, the Injection of MHC-mismatched iPSC-CMs into monkey hearts under immunosuppression elicited a strong immune response and tissue rejection. However, transplanting MHC-matched iPSC-CMs avoided immune-rejection and allowed graft survival for the 12-week duration of the experiment. Furthermore, iPSC-CMs transplanted following myocardial infarction integrated and electrically coupled with host cardiomyocytes and this permitted both the remuscularisation of damaged heart sections and the improvement of contractile function. The authors did note transient ventricular tachycardia in early time points after iPSC-CM injection, although the animals behaved normally and did not exhibit any signs blood pressure-related complications (syncope).

The application of MHC-matched iPSCs and their derivatives may represent the way forward for regenerative medicine, although the authors do note the requirement for further studies to confirm their exciting findings. These studies will include the establishment of the minimum amount of immunosuppression required, investigations into possible paracrine effects iPSC-CMs, the addition of extra iPSC lines, investigations into the causes of tachycardia, as well as the longer-term assessment of function and possible graft rejection.

Keep your eyes glued to the Stem Cells Portal to hear more about MHC-matched iPSCs and their application in tissue repair and regeneration!

References

  1. Bach FH, Bach ML, and Sondel PM. Differential function of major histocompatibility complex antigens in T-lymphocyte activation. Nature 1976;259:273-281.
  2. Petersdorf EW. The major histocompatibility complex: a model for understanding graft-versus-host disease. Blood 2013;122:1863-1872.
  3. Shiba Y, Gomibuchi T, Seto T, et al. Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature 2016;
  4. Shiba Y, Fernandes S, Zhu WZ, et al. Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature 2012;489:322-325.
  5. Laflamme MA, Chen KY, Naumova AV, et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat Biotechnol 2007;25:1015-1024.
  6. Zhang J, Klos M, Wilson GF, et al. Extracellular matrix promotes highly efficient cardiac differentiation of human pluripotent stem cells: the matrix sandwich method. Circ Res 2012;111:1125-1136.