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

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

Comprehensive Profiling of Secretome Formulations from Fetal- and Perinatal Human Amniotic Fluid Stem Cells

“…Notably, human amniotic fluid stem cells (hAFS) have been highlighted as promising therapeutic strategyin regenerative medicine. hAFS have been shown to be broadly multipotent in vitro and in vivo [ 16 , 27 , 28 ], contribute to the hematopoietic lineage following in utero transplantation [ 29 ] and engraft in injured organs while exerting immunomodulatory effects [ 26 , 30 ] and activating endogenous reparative responses, as comprehensively described in [ 31 ]. Our team and others have further demonstrated that hAFS release a secretome highly enriched with bioactive trophic molecules able to target different reparative mechanisms.…”

Perinatal Derivatives: Where Do We Stand? A Roadmap of the Human Placenta and Consensus for Tissue and Cell Nomenclature

“…Although the antigen surface expression is detected at the first passages (Di Trapani et al, 2013) and is gradually lost during expansion, cell selection makes hAFSC a peculiar population that maintains the ability to differentiate. Indeed, hAFSC can differentiate toward the hematopoietic (Ditadi et al, 2009;Loukogeorgakis et al, 2019), myogenic (Piccoli et al, 2012), and endothelial cells (Schiavo et al, 2015), not only in vitro but also in vivo and after secondary transplantation. In an elegant work, Xinaris and colleagues performed chimeric kidney organoids with hAFSC (after CD117 selection) and, strikingly, human cells contributed to the formation of glomerular structures, differentiating into podocytes (Xinaris et al, 2016).…”

Experimental and clinical progress of in utero hematopoietic cell transplantation therapy for congenital disorders

“…Peranteau et al ( 2007) demonstrated that after transplantation of high doses of allogeneic or congenic BM cells into fetal mice, only 30% of allogeneic recipients sustained long-term chimerism, whereas 100% of congenic recipients remained chimeric. Recently, studies by Shangaris et al (2018) and Loukogeorgakis et al (2019b) showed that 100% of congenic recipients remained macrochimerism compared to 29% or 0% of allogeneic recipients with microchimerism after in utero transplantation of amniotic fluid stem cells. These results strongly suggest the engraftment advantage of congenic stem cells over allogeneic stem cells and the existence of immune barriers resulting in the elimination of allogeneic cells after IUHCT.…”