Boosting Hematopoietic Engraftment after in Utero Transplantation through Vascular Niche Manipulation.
In 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.
Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, 391 Technology Way, Winston-Salem, NC 27157-1083, USA.
Saloomeh
S
Mokhtari
Experimental Station, University of Nevada Reno, Reno, NV 89503, USA.
Evan J
EJ
Colletti
Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, 391 Technology Way, Winston-Salem, NC 27157-1083, USA.
Anthony
A
Atala
Experimental Station, University of Nevada Reno, Reno, NV 89503, USA.
Esmail D
ED
Zanjani
Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, 391 Technology Way, Winston-Salem, NC 27157-1083, USA.
Christopher D
CD
Porada
Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, 391 Technology Way, Winston-Salem, NC 27157-1083, USA. Electronic address: galmeida@wakehealth.edu.
Graça
G
Almeida-Porada
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001805:Blood Transfusion, Intrauterine; D016026:Bone Marrow Transplantation; D051929:CD146 Antigen / Q000235:genetics / Q000276:immunology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000276:immunology; D042783:Endothelial Cells / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D057510:Endovascular Procedures; D005260:Female; D005333:Fetus; D015870:Gene Expression; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D011247:Pregnancy; D034561:Sheep, Domestic; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000276:immunology
D015415:Biomarkers; D051929:CD146 Antigen; D054377:Chemokine CXCL12; D040301:Vascular Endothelial Growth Factor Receptor-2