Loukogeorgakis_et_al-2019-STEM_CELLS.pdf (5.79 MB)

In utero transplantation of expanded autologous amniotic fluid stem cells results in long-term hematopoietic engraftment.

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journal contribution
posted on 08.01.2020 by Stavros P Loukogeorgakis, Panicos Shangaris, Enrica Bertin, Chiara Franzin, Martina Piccoli, Michela Pozzobon, Sindhu Subramaniam, Alfonso Tedeschi, Aimee G Kim, Haiying Li, Camila G Fachin, Andre IBS Dias, John D Stratigis, Nicholas J Ahn, Adrian J Thrasher, Paola Bonfanti, William H Peranteau, Anna L David, Alan W Flake, Paolo De Coppi
In utero transplantation (IUT) of hematopoietic stem cells (HSC) 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 sub-therapeutic, likely due to host fetal HSC out-competing their bone-marrow (BM) derived donor equivalents for space in the hematopoietic compartment. In the present study we demonstrate that amniotic fluid stem cells (AFSC; c-Kit+/Lin-) have hematopoietic characteristics and, thanks to their fetal origin, favourable proliferation kinetics in vitro and in vivo, which are maintained when the cells are expanded. IUT of autologous/congenic freshly-isolated or cultured AFSC resulted in stable mutli-lineage hematopoietic engraftment, far higher to that achieved with BM-HSC. Intravascular IUT of allogenic AFSC 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 AFSC 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 AFSC could be used as a stem cell/gene therapy platform for the in utero treatment of inherited disorders of hematopoiesis. SIGNIFICANCE STATEMENT: Amniotic fluid stem cells can be expanded without losing their hematopoietic characteristics In utero transplantation of allogenic AFSC results in adaptive immune response and donor cell rejection, due to failure of timely homing of donor cells to the host fetal thymus and lack of central tolerance induction. Autologous/congenic amniotic fluid stem cells can be transplanted in utero and result in stable, multi-lineage, long-term hematopoietic engraftment that is significantly higher to that achieved with bone marrow-derived cells and could be therapeutic in many inherited disorders of hematopoiesis. © AlphaMed Press 2019.