Cellular therapies supplement: the peritoneum as an ectopic site of hematopoiesis following in utero transplantation

Abstract

BACKGROUND In utero transplantation (IUT) has the potential to treat birth defects early before full development of the immune system. Relatively small grafts, that are not matched for major histocompatibility antigens, can be delivered even before onset of disease symptoms. IUT of hematopoietic stem cells is usually performed via intraperitoneal injection, yet the fate of donor cells in the peritoneal cavity is not fully understood. We review our recent work and present new data demonstrating that the peritoneum can be a site of ectopic hematopoiesis with implications for IUT and immune tolerance induction. STUDY DESIGN AND METHODS Haplogeneic and allogeneic fetal transplants were performed in mice and engraftment tracked by flow cytometry. Immune tolerance was studied by mixed lymphocyte reactions and skin transplantation. Adult syngeneic murine transplants and xenogeneic human into immunodeficient-mouse transplants were performed to follow hematopoietic retention in the peritoneum and engraftment of the bone marrow. RESULTS Although most transplanted cells rapidly clear the peritoneum, hematopoietic cells and cells with the phenotype of hematopoietic precursors can remain in the peritoneal cavity for months after transplant. The presence of donor cells in the peritoneum can contribute to donor-specific tolerance but sufficient peripheral blood chimerism is required to ensure acceptance of donor skin grafts. CONCLUSION Ectopic hematopoiesis and the survival of stem cells in the peritoneum offers the possibility of better using the peritoneal cavity to delivery stem cells and foster the development of immune tolerance to alloantigens or other foreign antigens.

The Intravenous Route of Injection Optimizes Engraftment and Survival in the Murine Model of In Utero Hematopoietic Cell Transplantation

“…The inefficient migration of donor cells to the FL after i.p. IUHCT is supported by the study of Muench et al [35], which demonstrated that 62% and 50% of donor cells remained in the murine peritoneal cavity 24 hours and 1 week after IUHCT, respectively, with enriched HSCs. The persistence of donor cells in the perihepatic space and peritoneal cavity after i.h.…”

Hematopoietic Stem and Progenitor Cells as Effectors in Innate Immunity

“…Many tissues, however, can accommodate hematopoiesis [ 23 ] and thus may contain the essential elements of a stem cell niche. EMH has been reported in such diverse tissues as the skin, joint, urinary bladder, peritoneum, pleura, testes, adrenal glands, and gastrointestinal tract [ 24 – 31 ]. Myelofibrosis, inflammation, and infection are frequent underlying causes of EMH.…”

Peritoneal Submesothelial Stromal Cells Support Hematopoiesis and Differentiate into Osteogenic and Adipogenic Cell Lineages

“…Extramedullary hematopoiesis exists in different tissues and it is frequently correlated with myelopoiesis [Oliveira et al, 2007;Aguado et al, 2011;Muench et al, 2011]. Inside the peritoneal cavity, extramedullary hematopoiesis has been associated with case reports and clinical disorders.…”

“…Considering that the peritoneal cavity supports extramedullary hematopoiesis in distinct situations [Holden et al, 2006;Muench et al, 2011], we investigated the capacity of these peritoneal stromal cells to support hematopoiesis using a coculture system. Bone marrow-derived hematopoietic cells were cultured with peritoneal stromal cells at passage 3.…”