title: Synergistic actions of hematopoietic and mesenchymal stem/progenitor cells in vascularizing bioengineered tissues.
abstract: Poor angiogenesis is a major road block for tissue repair. The regeneration of virtually all tissues is limited by angiogenesis, given the diffusion of nutrients, oxygen, and waste products is limited to a few hundred micrometers. We postulated that co-transplantation of hematopoietic and mesenchymal stem/progenitor cells improves angiogenesis of tissue repair and hence the outcome of regeneration. In this study, we tested this hypothesis by using bone as a model whose regeneration is impaired unless it is vascularized. Hematopoietic stem/progenitor cells (HSCs) and mesenchymal stem/progenitor cells (MSCs) were isolated from each of three healthy human bone marrow samples and reconstituted in a porous scaffold. MSCs were seeded in micropores of 3D calcium phosphate (CP) scaffolds, followed by infusion of gel-suspended CD34(+) hematopoietic cells. Co-transplantation of CD34(+) HSCs and CD34(-) MSCs in microporous CP scaffolds subcutaneously in the dorsum of immunocompromised mice yielded vascularized tissue. The average vascular number of co-transplanted CD34(+) and MSC scaffolds was substantially greater than MSC transplantation alone. Human osteocalcin was expressed in the micropores of CP scaffolds and was significantly increased upon co-transplantation of MSCs and CD34(+) cells. Human nuclear staining revealed the engraftment of transplanted human cells in vascular endothelium upon co-transplantation of MSCs and CD34(+) cells. Based on additional in vitro results of endothelial differentiation of CD34(+) cells by vascular endothelial growth factor (VEGF), we adsorbed VEGF with co-transplanted CD34(+) and MSCs in the microporous CP scaffolds in vivo, and discovered that vascular number and diameter further increased, likely owing to the promotion of endothelial differentiation of CD34(+) cells by VEGF. Together, co-transplantation of hematopoietic and mesenchymal stem/progenitor cells may improve the regeneration of vascular dependent tissues such as bone, adipose, muscle and dermal grafts, and may have implications in the regeneration of internal organs.
authors.affiliation: Columbia University Medical Center, Tissue Engineering and Regenerative Medicine Laboratory, College of Dental Medicine, New York, New York, United States of America.
authors.forename: Eduardo K
authors.initials: EK
authors.lastname: Moioli
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clark
authors.forename: Mo
authors.initials: M
authors.lastname: Chen
authors.forename: James E
authors.initials: JE
authors.lastname: Dennis
authors.forename: Helaman P
authors.initials: HP
authors.lastname: Erickson
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Mao
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002469:Cell Separation; D003094:Collagen / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004727:Endothelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015675:Osteocalcin / Q000378:metabolism; D023822:Tissue Engineering; D054457:Tissue Scaffolds; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D018952:Antigens, CD34; D042461:Vascular Endothelial Growth Factor A; D015675:Osteocalcin; D003094:Collagen