Influence of a dual-injection regimen, plerixafor and CXCR4 on in utero hematopoietic stem cell transplantation and engraftment with use of the sheep model. Cytotherapy 2014 Sep;16(9):1280-93
Date
08/12/2014Pubmed ID
25108653Pubmed Central ID
PMC4131210DOI
10.1016/j.jcyt.2014.05.025Scopus ID
2-s2.0-84905484443 (requires institutional sign-in at Scopus site) 8 CitationsAbstract
BACKGROUND AIMS: Inadequate engraftment of hematopoietic stem cells (HSCs) after in utero HSC transplantation (IUHSCT) remains a major obstacle for the prenatal correction of numerous hereditary disorders. HSCs express CXCR4 receptors that allow homing and engraftment in response to stromal-derived factor 1 (SDF-1) ligand present in the bone marrow stromal niche. Plerixafor, a mobilization drug, works through the interruption of the CXCR4-SDF-1 axis.
METHODS: We used the fetal sheep large-animal model to test our hypotheses that (i) by administering plerixafor in utero before performing IUHSCT to release fetal HSCs and thus vacating recipient HSC niches, (ii) by using human mesenchymal stromal/stem cells (MSCs) to immunomodulate and humanize the fetal BM niches and (iii) by increasing the CXCR4(+) fraction of CD34(+) HSCs, we could improve engraftment. Human cord blood-derived CD34(+) cells and human bone marrow-derived MSCs were used for these studies.
RESULTS: When MSCs were transplanted 1 week before CD34(+) cells with plerixafor treatment, we observed 2.80% donor hematopoietic engraftment. Combination of this regimen with additional CD34(+) cells at the time of MSC infusion increased engraftment levels to 8.77%. Next, increasing the fraction of CXCR4(+) cells in the CD34(+) population albeit transplanting at a late gestation age was not beneficial. Our results show engraftment of both lymphoid and myeloid lineages.
CONCLUSIONS: Prior MSC and HSC cotransplantation followed by manipulation of the CXCR4-SDF-1 axis in IUHSCT provides an innovative conceptual approach for conferring competitive advantage to donor HSCs. Our novel approach could provide a clinically relevant approach for enhancing engraftment early in the fetus.
Author List
Goodrich AD, Varain NM, Jeanblanc CM, Colon DM, Kim J, Zanjani ED, Hematti PAuthor
Peiman Hematti MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntigens, CD34
Benzylamines
Cell Differentiation
Cell Lineage
Cells, Cultured
Chemokine CXCL12
Clinical Protocols
Disease Models, Animal
Female
Fetus
Genetic Diseases, Inborn
Graft Survival
Hematopoietic Stem Cell Transplantation
Heterocyclic Compounds
Humans
Immunomodulation
Pregnancy
Receptors, CXCR4
Sheep
