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A Safe and Effective Means to Produce and Transplant iPSC-Derived Progenitors?

Review of “Tumor-Free Transplantation of Patient-Derived Induced Pluripotent Stem Cell Progeny for Customized Islet Regeneration” from Stem Cells Translational Medicine by Stuart P. Atkinson

The differentiation of patient-specific induced pluripotent stem cells (iPSCs) into has the potential to provide differentiated cells to test drugs, model diseases, and, most importantly, to replace lost or damaged tissues. However, genome integrating viral vectors and oncogenic transcription factors are still key parts of many reprogramming schemes, and many early differentiation studies need to be confirmed using iPSCs generated using safer non-integrating viral vectors.

This has led the group of Yasuhiro Ikeda (Mayo Clinic College of Medicine, USA) to work out a strategy to produce safe and effective cells from iPSCs. In their new Stem Cells Translational Medicine study they show how this strategy can be safely applied to replace the pancreatic cells lost via autoimmune destruction in type 1 diabetes mellitus (T1D) [1].

Pancreatic endoderm progenitor cells can mediate islet regeneration in mice [2, 3] and the study used such cells differentiated from iPSCs [2, 4] throughout the study. However, their initial finding demonstrated that progenitor derived from iPSCs generated using lentiviral gene transduction led to the high incidence of highly aggressive tumors in immunodeficient mice after transplantation under the kidney capsule. Even more worryingly, removal of tumors led to the appearance of metastatic lesions (See figure - anti-human antigen antibody identifies human iPSC-derived cells in mouse tumors and metastases). Time to find another strategy!

After some careful thought, the authors decided to derive transgene-free iPSCs (TGF-iPSCs) using non-integrating Sendai viral reprogramming vectors, including from patients with type 1 and 2 diabetes [5]. They then combined this with trypsin-mediated cell dissociation of differentiated progenitors to eliminate contamination by pluripotent cells (which do not survive well after single cell dissociation [6]). This led to some great results – no tumor formation at 3 and 8 months after transplantation, and, importantly, evidence of the regeneration of human-like islets.

A safe and effective strategy for the transplantation of iPSC-derived progenitors: what more can you ask for? Clinical translation is the obvious answer, and hopefully this research will represent an important step in reducing the risk of stem cell treatment for diabetes, as well as other diseases. Are we looking at the way to safely step forward from the bench to the bedside?

Discussion Points

  • Does this represent the safest means to produce and use iPSCs/iPSC-derived cells?
  • What other strategies can be implemented to improve safety?
  • Will the same safety profile and functionality occur with other progenitors generated and transplanted using this strategy?


  1. El Khatib MM, Ohmine S, Jacobus EJ, et al. Tumor-Free Transplantation of Patient-Derived Induced Pluripotent Stem Cell Progeny for Customized Islet Regeneration. Stem Cells Translational Medicine 2016;5:694-702.
  2. Kroon E, Martinson LA, Kadoya K, et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat Biotechnol 2008;26:443-452.
  3. Rezania A, Bruin JE, Riedel MJ, et al. Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes 2012;61:2016-2029.
  4. Thatava T, Nelson TJ, Edukulla R, et al. Indolactam V/GLP-1-mediated differentiation of human iPS cells into glucose-responsive insulin-secreting progeny. Gene Ther 2011;18:283-293.
  5. Kudva YC, Ohmine S, Greder LV, et al. Transgene-free disease-specific induced pluripotent stem cells from patients with type 1 and type 2 diabetes. Stem Cells Transl Med 2012;1:451-461.
  6. Watanabe K, Ueno M, Kamiya D, et al. A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat Biotechnol 2007;25:681-686.