Abstract
In utero transplantation (IUT) of hematopoietic stem cells (HSCs) has been proposed as a strategy for the prenatal treatment of congenital hematological diseases. However, levels of long‐term hematopoietic engraftment achieved in experimental IUT to date are subtherapeutic, likely due to host fetal HSCs outcompeting their bone marrow (BM)‐derived donor equivalents for space in the hematopoietic compartment. In the present study, we demonstrate that amniotic fluid stem cells (AFSCs; c‐Kit+/Lin−) have hematopoietic characteristics and, thanks to their fetal origin, favorable proliferation kinetics in vitro and in vivo, which are maintained when the cells are expanded. IUT of autologous/congenic freshly isolated or cultured AFSCs resulted in stable multilineage hematopoietic engraftment, far higher to that achieved with BM‐HSCs. Intravascular IUT of allogenic AFSCs was not successful as recently reported after intraperitoneal IUT. Herein, we demonstrated that this likely due to a failure of timely homing of donor cells to the host fetal thymus resulted in lack of tolerance induction and rejection. This study reveals that intravascular IUT leads to a remarkable hematopoietic engraftment of AFSCs in the setting of autologous/congenic IUT, and confirms the requirement for induction of central tolerance for allogenic IUT to be successful. Autologous, gene‐engineered, and in vitro expanded AFSCs could be used as a stem cell/gene therapy platform for the in utero treatment of inherited disorders of hematopoiesis. stem cells 2019;37:1176–1188
Highlights
In utero transplantation (IUT) of hematopoietic stem cells (HSCs) is a potential nonmyeloablative strategy for the treatment of many hematologic disorders [1, 2]
IUT of autologous/congenic freshly isolated or cultured amniotic fluid stem cells (AFSCs) resulted in stable multilineage hematopoietic engraftment, far higher to that achieved with bone marrow (BM)-HSCs
We focused our analysis on the key hematopoietic regulators dams at E13 with (B) a high level of purity based on CD117 expression. (C): The phenotype of AFSC includes CD45, Sca-1, CD34, and major histocompatibility complex class I (n = 8). (D, E): Gene array analysis of AFSC compared with adult bone marrow-derived hematopoietic stem cells (BM-HSCs)
Summary
In utero transplantation (IUT) of hematopoietic stem cells (HSCs) is a potential nonmyeloablative strategy for the treatment of many hematologic disorders [1, 2]. Engraftment of allogenic HSCs requires both induction of donor-specific immunologic tolerance through thymic processing of donor antigen [3,4,5,6] and successful competition of donor HSCs for receptive niches in the robust, nonmyeloablated fetal hematopoietic compartment [7]. Engraftment of donor cells after IUT can be accomplished across full major histocompatibility complex (MHC) barriers under specific circumstances in both murine [8, 9] and large animal models [10,11,12]. In the murine model of allogenic IUT, we and others have shown that successful engraftment of adult bone marrow (BM) cells requires effective delivery of a relatively large dose of cells within a specific gestational age time window to achieve tolerance [13,14,15].
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