In Utero Transplantation of Expanded Autologous Amniotic Fluid Stem Cells Results in Long-Term Hematopoietic Engraftment: In Utero Transplantation of AFSC

TY - JOUR

T1 - In Utero Transplantation of Expanded Autologous Amniotic Fluid Stem Cells Results in Long-Term Hematopoietic Engraftment

T2 - In Utero Transplantation of AFSC

AU - Loukogeorgakis, Stavros P.

AU - Shangaris, Panicos

AU - Bertin, Enrica

AU - Franzin, Chiara

AU - Piccoli, Martina

AU - Pozzobon, Michela

AU - Subramaniam, Sindhu

AU - Tedeschi, Alfonso

AU - Kim, Aimee G.

AU - Li, Haiying

AU - Fachin, Camila G.

AU - Dias, Andre I. B. S.

AU - Stratigis, John D.

AU - Ahn, Nicholas J.

AU - Thrasher, Adrian J.

AU - Bonfanti, Paola

AU - Peranteau, William H.

AU - David, Anna L.

AU - Flake, Alan W.

AU - De Coppi, Paolo

PY - 2019/5/22

Y1 - 2019/5/22

N2 - 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.

AB - 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.

KW - Autologous stem cell transplantation

KW - Cell culture

KW - Fetal stem cells

KW - Hematopoiesis

KW - Transplantation tolerance

UR - http://www.scopus.com/inward/record.url?scp=85070447637&partnerID=8YFLogxK

U2 - 10.1002/stem.3039

DO - 10.1002/stem.3039

M3 - Article

SN - 1066-5099

VL - 37

SP - 1176

EP - 1188

JO - Stem Cells

JF - Stem Cells

IS - 9

ER -