title: Influence of a dual-injection regimen, plerixafor and CXCR4 on in utero hematopoietic stem cell transplantation and engraftment with use of the sheep model.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Agriculture, Nutrition, and Veterinary Science, University of Nevada-Reno, Reno, Nevada, USA.
authors.forename: A Daisy
authors.initials: AD
authors.lastname: Goodrich
authors.affiliation: Department of Agriculture, Nutrition, and Veterinary Science, University of Nevada-Reno, Reno, Nevada, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Varain
authors.affiliation: Department of Agriculture, Nutrition, and Veterinary Science, University of Nevada-Reno, Reno, Nevada, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Jeanblanc
authors.affiliation: Department of Agriculture, Nutrition, and Veterinary Science, University of Nevada-Reno, Reno, Nevada, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Colon
authors.affiliation: Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Jaehyup
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Agriculture, Nutrition, and Veterinary Science, University of Nevada-Reno, Reno, Nevada, USA.
authors.forename: Esmail D
authors.initials: ED
authors.lastname: Zanjani
authors.affiliation: Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA; Carbone Cancer Center, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA. Electronic address: pxh@medicine.wisc.edu.
authors.forename: Peiman
authors.initials: P
authors.lastname: Hematti
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001596:Benzylamines; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D002985:Clinical Protocols; D000080027:Cyclams; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus; D030342:Genetic Diseases, Inborn / Q000628:therapy*; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006571:Heterocyclic Compounds / Q000008:administration & dosage*; D006801:Humans; D056747:Immunomodulation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D011247:Pregnancy; D019718:Receptors, CXCR4 / Q000008:administration & dosage*; D012756:Sheep
chemical_list: D018952:Antigens, CD34; D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor
keywords: CXCR4; SDF-1; hematopoietic stem cell transplantation; in utero transplantation; plerixafor; sheep model
references.citation: Exp Hematol. 2010 Jun;38(6):516-525.e4
references.pmid: 20227460
references.citation: J Clin Invest. 2011 Feb;121(2):582-92
references.pmid: 21245575
references.citation: Cytotherapy. 2009;11(5):503-15
references.pmid: 19728189
references.citation: J Anim Sci. 2012 Jan;90(1):159-70
references.pmid: 21841083
references.citation: Exp Hematol. 2009 Dec;37(12):1445-53
references.pmid: 19772890
references.citation: Blood. 2004 Mar 1;103(5):1941-8
references.pmid: 14592834
references.citation: J Surg Res. 1999 May 1;83(1):44-7
references.pmid: 10210641
references.citation: Stem Cells Transl Med. 2012 Jan;1(1):70-8
references.pmid: 23197643
references.citation: Cytotherapy. 2012 May;14(5):516-21
references.pmid: 22458957
references.citation: Transplant Proc. 1993 Feb;25(1 Pt 2):1246-7
references.pmid: 8442104
references.citation: Chimerism. 2011 Apr;2(2):55-7
references.pmid: 21912720
references.citation: Blood. 2008 Dec 15;112(13):5245-53
references.pmid: 18796629
references.citation: Haematologica. 2010 Apr;95(4):542-50
references.pmid: 20145267
references.citation: Exp Hematol. 2008 Dec;36(12):1739-49
references.pmid: 19007686
references.citation: Haematologica. 2008 Mar;93(3):321-4
references.pmid: 18310535
references.citation: Blood. 2006 May 1;107(9):3772-8
references.pmid: 16439684
references.citation: Biol Blood Marrow Transplant. 2009 Jan;15(1):39-46
references.pmid: 19135941
references.citation: Cytotherapy. 2013 May;15(5):525-35
references.pmid: 23415921
references.citation: Blood. 2011 Dec 15;118(25):6580-90
references.pmid: 21989987
references.citation: Haematologica. 2013 Apr;98(4):505-13
references.pmid: 22801967
references.citation: Science. 1986 Aug 15;233(4765):776-8
references.pmid: 2874611
references.citation: Pediatr Blood Cancer. 2012 Jul 15;59(1):197-8
references.pmid: 22012661
references.citation: J Exp Med. 2003 Nov 3;198(9):1391-402
references.pmid: 14597738
references.citation: Leukemia. 2007 Mar;21(3):568-70
references.pmid: 17252011
references.citation: Minerva Ginecol. 2011 Aug;63(4):387-98
references.pmid: 21747347
references.citation: Swiss Med Wkly. 2007 Mar 2;137 Suppl 155:14S-19S
references.pmid: 17874495
references.citation: Haematologica. 2008 Nov;93(11):1607-10
references.pmid: 18978297
references.citation: J Clin Invest. 2009 Sep;119(9):2590-600
references.pmid: 19652363
references.citation: Cytotherapy. 2009;11(3):278-88
references.pmid: 19308773
references.citation: Br J Haematol. 2014 Jul;166(2):268-78
references.pmid: 24673111
references.citation: Haematologica. 2011 Jul;96(7):1072-6
references.pmid: 21393326
references.citation: Haematologica. 2010 Jan;95(1):47-56
references.pmid: 19713224
references.citation: J Nippon Med Sch. 2009 Aug;76(4):198-208
references.pmid: 19755795
references.citation: Haematologica. 2012 May;97(5):651-60
references.pmid: 22058199
references.citation: Blood. 1995 Dec 1;86(11):4353-66
references.pmid: 7492797
references.citation: Haematologica. 2010 Apr;95(4):651-9
references.pmid: 20179086
references.citation: Clin Pharmacokinet. 2014 Mar;53(3):247-259
references.pmid: 24142388
references.citation: J Exp Med. 2005 Apr 18;201(8):1307-18
references.pmid: 15837815
references.citation: Blood. 2013 Oct 24;122(17):3074-81
references.pmid: 23996087
references.citation: Stem Cells Dev. 2004 Dec;13(6):677-84
references.pmid: 15684835
references.citation: Cytotherapy. 2006;8(4):315-7
references.pmid: 16923606
references.citation: Nat Med. 2000 Nov;6(11):1282-6
references.pmid: 11062543
references.citation: Blood. 1998 May 15;91(10):3681-7
references.pmid: 9573004
references.citation: J Exp Med. 1964 Jan 1;119:955-64
references.pmid: 14176293
references.citation: Stem Cells. 1997;15 Suppl 1:79-92; discussion 93
references.pmid: 9368328
references.citation: Blood. 1995 Feb 1;85(3):833-41
references.pmid: 7833485
references.citation: Blood. 2005 Dec 1;106(12):4002-8
references.pmid: 16105977
references.citation: PLoS One. 2007 May 02;2(5):e416
references.pmid: 17476338
references.citation: Blood. 2006 Mar 1;107(5):1878-87
references.pmid: 16282345
references.citation: Cell Transplant. 2008;17(5):495-506
references.pmid: 18714669
references.citation: Exp Hematol. 2012 Jun;40(6):436-44
references.pmid: 22306296
references.citation: Haematologica. 2011 Jan;96(1):134-41
references.pmid: 21071499
references.citation: J Am Assoc Lab Anim Sci. 2011 Jul;50(4):445-53
references.pmid: 21838970
references.citation: Exp Hematol. 1997 Feb;25(2):114-21
references.pmid: 9015211
references.citation: Blood. 2006 Mar 1;107(5):2180-3
references.pmid: 16278307
references.citation: Exp Hematol. 2008 Mar;36(3):350-9
references.pmid: 18179856
references.citation: J Immunol. 2013 Dec 15;191(12):6241-9
references.pmid: 24244025
references.citation: Exp Hematol. 2013 Aug;41(8):749-758.e5
references.pmid: 23612043
references.citation: Transplantation. 2005 Jun 15;79(11):1607-14
references.pmid: 15940052
references.citation: Blood Rev. 2012 Nov;26(6):241-6
references.pmid: 22958984