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Exploring the Immunogenicity of Human iPSC-derived Cells

Review of “Myogenic progenitor cells derived from human induced pluripotent stem cell are immune-tolerated in humanized mice” from STEM CELLS Translational Medicine by Stuart P. Atkinson

The central promise of human induced pluripotent stem cell (iPSC)-based therapies is the lack of immune response; however, the complexities faced when using humanized mouse models have limited any wide-ranging evaluations of immunogenicity. A previous study using bone-marrow, liver, thymus-humanized (Hu-BLT) mice reported the immunogenic nature of some autologous hiPSC‐derived cells [1] – in this case, smooth muscle cells raised an immune response, although retinal pigment epithelial cells did not. However, this study only assessed autologous T cell infiltration and not the actual survival of the graft.

In a new STEM CELLS Translational Medicine article [2], researchers from the laboratory of Christian Beauséjour (Centre de Recherche du CHU Ste‐Justine, Montréal, Québec, Canada) characterized the immunogenicity of human iPSC-derived skeletal muscle cells. Encouragingly, Benabdallah et al. now report that while transplanted cells become infiltrated by immune cells after transplantation, this does not negatively impact engraftment.

The authors of this exciting new study employed two different humanized mouse models, one model generated by the adoptive transfer of peripheral blood mononuclear cells (Hu-AT, using NSG‐SGM3 mice [3]) and another generated by the cotransplantation of hematopoietic stem cells and human thymic tissue (Hu-BLT, using NSG mice [4]). While allogeneic muscle cell grafts became highly infiltrated with human T cells following intramuscular transplantation and mainly rejected, autologous muscle cells engrafted well within the same site; more interestingly, the humanized mice tolerated grafts of hiPSC-derived myogenic progenitor cells (MPCs – display broad similarities to primary human myoblasts) despite being infiltrated by autologous T cells. Overall, the authors provide evidence that their conditions for the generation and maintenance of MPCs [5, 6] render them relatively non-immunogenic.

The authors note that these findings provide evidence for the prediction of immunogenicity of cells by means other than human immune cell infiltration in skeletal muscle and the therapeutic application of usage of hiPSC‐derived myogenic progenitor cells.

For more on the immunogenicity of human iPSC-derived cells and the consequences for their therapeutic application, stay tuned to the Stem Cells Portal!

References

  1. Zhao T, Zhang Z-n, Westenskow PD, et al., Humanized Mice Reveal Differential Immunogenicity of Cells Derived from Autologous Induced Pluripotent Stem Cells. Cell Stem Cell 2015;17:353-359.
  2. Benabdallah B, Désaulniers-Langevin C, Goyer M-L, et al., Myogenic progenitor cells derived from human induced pluripotent stem cell are immune-tolerated in humanized mice. STEM CELLS Translational Medicine 2021;10:267-277.
  3. Moquin-Beaudry G, Colas C, Li Y, et al., The Tumor-Immune Response Is Not Compromised by Mesenchymal Stromal Cells in Humanized Mice. The Journal of Immunology 2019;203:2735.
  4. Shultz LD, Brehm MA, Garcia-Martinez JV, et al., Humanized mice for immune system investigation: progress, promise and challenges. Nature Reviews Immunology 2012;12:786-798.
  5. Goudenege S, Lebel C, Huot NB, et al., Myoblasts Derived From Normal hESCs and Dystrophic hiPSCs Efficiently Fuse With Existing Muscle Fibers Following Transplantation. Molecular Therapy 2012;20:2153-2167.
  6. Fujii I, Matsukura M, Ikezawa M, et al., Adenoviral mediated MyoD gene transfer into fibroblasts: Myogenic disease diagnosis. Brain and Development 2006;28:420-425.