Boosting Hematopoietic Engraftment after in Utero Transplantation through Vascular Niche Manipulation

Abstract

SummaryIn utero hematopoietic stem/progenitor cell transplantation (IUHSCT) has only been fully successful in the treatment of congenital immunodeficiency diseases. Using sheep as a large animal model of IUHSCT, we demonstrate that administration of CD146+CXCL12+VEGFR2+ or CD146+CXCL12+VEGFR2− cells prior to, or in combination with, hematopoietic stem/progenitor cells (HSC), results in robust CXCL12 production within the fetal marrow environment, and significantly increases the levels of hematopoietic engraftment. While in the fetal recipient, donor-derived HSC were found to reside within the trabecular bone, the increased expression of VEGFR2 in the microvasculature of CD146+CXCL12+VEGFR2+ transplanted animals enhanced levels of donor-derived hematopoietic cells in circulation. These studies provide important insights into IUHSCT biology, and demonstrate the feasibility of enhancing HSC engraftment to levels that would likely be therapeutic in many candidate diseases for IUHSCT.

The Bone Marrow Pericyte: An Orchestrator Of Vascular Niche

“…Mokhtari et al . demonstrated that transplanted human CD146 + BM cells could increase CXCL-12 production in the large animal fetal recipient, triggering HSC reconstitution [ 85 ]. That process could mimic a physiological one.…”

Investigating Optimal Autologous Cellular Platforms for Prenatal or Perinatal Factor VIII Delivery to Treat Hemophilia A

“…In addition, the high proliferative potential and rapid doubling times ensure that clinically relevant numbers of UCT-derived cells, i.e., a total of 10 7 (clinically employed dose: 10 7 –10 8 cells/kg fetal weight) could quickly be obtained. In similarity to AF-MSC, in utero transplantation of MSC and EPC results in long term engraftment in treated animals without any adverse effects ( Colletti et al, 2009 ; Wood et al, 2012 ; Mokhtari et al, 2016 ). Thus, these qualities combine to make UCT-MSC and UCT-EPC particularly attractive candidates for cellular delivery vehicles for FVIII, and likely other gene products as well.…”

“…Human umbilical vein endothelial cells (Lonza, Walkersville, MD, United States) and HHSEC (Science Cell Research Laboratories, Carlsbad, CA, United States) were purchased and expanded in EGM-2 according to manufacturer’s instructions, as previously described in detail ( Sanada et al, 2013 ; Mokhtari et al, 2016 ).…”

In utero Therapy for the Treatment of Sickle Cell Disease: Taking Advantage of the Fetal Immune System

“…Additionally, co-transplantation with stroma can selectively influence the expression of homing receptors and ultimately improve engraftment, as hematopoietic activity increases considerably after stromal establishment (Flake and Zanjani, 1999). Indeed, co-transplanted stromal cells expressing CD146, CXCL12, and VEGF led to improved engraftment in sheep (Mokhtari et al, 2016).…”