Mesenchymal stem cells rescue CD34+ cells from radiation-induced apoptosis and sustain hematopoietic reconstitution after coculture and cografting in lethally irradiated baboons: is autologous stem cell therapy in nuclear accident settings hype or reality?

Abstract

Summary:Autologous stem cell therapy (ACT) has been proposed to prevent irradiated victims from bone marrow (BM) aplasia by grafting hematopoietic stem and progenitor cells (HSPCs) collected early after damage, provided that a functional graft of sufficient size could be produced ex vivo. To address this issue, we set up a baboon model of cell therapy in which autologous peripheral blood HSPCs collected before lethal total body irradiation were irradiated in vitro (2.5 Gy, D 0 1 Gy) to mimic the cell damage, cultured in small numbers for a week in a serumfree medium in the presence of antiapoptotic cytokines and mesenchymal stem cells (MSCs) and then cografted. Our study shows that baboons cografted with expanded cells issued from 0.75 and 1 Â 10 6 /kg irradiated CD34 þ cells and MSCs (n ¼ 2) exhibited a stable long-term multilineage engraftment. Hematopoietic recovery became uncertain when reducing the CD34 þ cell input (0.4 Â 10 6 /kg CD34 þ cells; n ¼ 3). However, platelet recovery was accelerated in all surviving cografted animals, when compared with baboons transplanted with unirradiated, unmanipulated CD34 þ cells (0.5-1 Â 10 6 / kg, n ¼ 4). Baboons grafted with MSCs alone (n ¼ 3) did not recover. In all cases, the nonhematopoietic toxicity remained huge. This baboon study suggests that ACT feasibility is limited.

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“…We found that HKMT protected bone marrow structure and restored the number of nucleated cells. CD34+ hemopoietic stem cells (HSCs) were the source of almost all the blood cells and immunocytes [27]. Our data also showed that HKMT increased the number of HSCs in bone marrow after irradiation.…”

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“…Further analyses in a primate model found detectable levels of allogeneic GFP-labeled MSCs in irradiated bone marrow samples up to 80 days after infusion, correlating with the repair of radiation damage and increased survival times [42]. Co-transplantation of MSCs with hematopoietic stem cells resulted in a stable multi-lineage engraftment and hematopoietic recovery [37,43]. It has been suggested that transplantation of MSCs alone without the addition of hematopoietic stem cells could also recover irradiated bone marrow and even result in improved survival [38,44].…”

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