Donor derived hematopoietic stem cell niche transplantation facilitates mixed chimerism mediated donor specific tolerance

Abstract

Compelling experimental evidence confirms that the robustness and longevity of mixed chimerism (MC) relies on the persistence and availability of donor-derived hematopoietic stem cell (HSC) niches in recipients. Based on our prior work in rodent vascularized composite allotransplantation (VCA) models, we hypothesize that the vascularized bone components in VCA bearing donor HSC niches, thus may provide a unique biologic opportunity to facilitate stable MC and transplant tolerance. In this study, by utilizing a series of rodent VCA models we demonstrated that donor HSC niches in the vascularized bone facilitate persistent multilineage hematopoietic chimerism in transplant recipients and promote donor-specific tolerance without harsh myeloablation. In addition, the transplanted donor HSC niches in VCA facilitated the donor HSC niches seeding to the recipient bone marrow compartment and contributed to the maintenance and homeostasis of stable MC. Moreover, this study provided evidences that chimeric thymus plays a role in MC-mediated transplant tolerance through a mechanism of thymic central deletion. Mechanistic insights from our study could lead to the use of vascularized donor bone with pre-engrafted HSC niches as a safe, complementary strategy to induce robust and stable MC-mediated tolerance in VCA or solid organ transplantation recipients.

Novel cell-based strategies for immunomodulation in vascularized composite allotransplantation

“…Mixed chimerism can be induced by transferring donor hematopoietic stem cells (HSCs) from bone marrow or cytokine-mobilized peripheral stem cells. However, additional conditioning is required to create a niche for donor HSC engraftment, which can generate toxic effects [21 ▪▪ ]. Moreover, mixed chimerism alone is not sufficient for long-term maintenance of tolerance and adjuvant approaches are necessary [22].…”

Efficacy of Engraftment and Safety of Human Umbilical Di-Chimeric Cell (HUDC) Therapy after Systemic Intraosseous Administration in an Experimental Model

“…In response to these challenges, cell-based therapies have emerged as a promising avenue. By leveraging the immunomodulatory properties of human stem cells and triggering mixed chimerism induction, these novel approaches aim to induce immunomodulation and alleviate the reliance on conventional immunosuppressive therapies [10,11].…”