Production of cells from iPS cells that induce immune tolerance — Hokkaido University successfully achieves graft rejection control in mice

The research group led by Professor Kenichiro Seino of the Institute for Genetic Medicine and Graduate Student Tomoki Murata of the Graduate School of Medicine at Hokkaido University announced that they have succeeded in controlling the rejection associated with organ transplantation by generating induced hematopoietic stem and progenitor cells (iHSPCs) from donor mouse induced pluripotent stem (iPS) cells for transplantation into recipient mice. They achieved efficient induction of iHSPC differentiation by introducing two types of transcription factors into mouse iPS cells. Mice that received the iHSPC injection survived for more than 20 weeks, and it was confirmed that the transplanted donor iPS cells and skin fragments continued to engraft even without the administration of immunosuppressants. Contributions to iPS-cell-based transplantation medicine is expected. The results were published in the May 24th issue of the international academic journal American Journal of Transplantation.

In most cases of organ transplantation, immune rejection occurs, requiring the recipient to take immunosuppressants for life. Immunosuppressants are also necessary following allogeneic iPS cell transplantations. Despite this, researchers have already successfully devised a method for inducing immune tolerance in human patients by transplanting donor hematopoietic stem cells to create a state in which blood cells coexist temporarily or permanently in the recipient (chimera state).

To induce immune tolerance in mice, the research group created a chimera state in the animals and investigated the engraftment rate of skin and iPS cells using allografts.

First, they examined multiple molecules to determine which of them should be introduced into iPS cells to induce iHSPC differentiation. They clarified that the introduction of two transcription factors, Lhx2 and Hox4, which are reported to be important for the differentiation and induction of blood cells, provided positive results. After the iHSPCs were injected into recipient mice, they survived for more than 20 weeks (even after temporary immunosuppression), and the chimera state was induced.

Furthermore, when donor iPS cells and syngeneic skin pieces were transplanted into these mice, the skin pieces survived in the absence of immunosuppressants. The injection of iHSPCs differentiated from donor iPS cells succeeded in creating immune tolerance in recipient mice.

Seino stated, "In the future, I would like to conduct research aimed at reducing pretreatments (such as irradiation) before transplantation and developing methods to induce immune tolerance in autoimmune diseases."

Journal Information
Publication: American Journal of Transplantation
Title: Induced pluripotent stem cell-derived hematopoietic stem and progenitor cells induce mixed chimerism and donor-specific allograft tolerance
DOI: 10.1016/j.ajt.2023.05.020