title: Adipose-Derived Stem Cell-Seeded Hydrogels Increase Endogenous Progenitor Cell Recruitment and Neovascularization in Wounds.
abstract: Adipose-derived mesenchymal stem cells (ASCs) are appealing for cell-based wound therapies because of their accessibility and ease of harvest, but their utility is limited by poor cell survival within the harsh wound microenvironment. In prior work, our laboratory has demonstrated that seeding ASCs within a soft pullulan-collagen hydrogel enhances ASC survival and improves wound healing. To more fully understand the mechanism of this therapy, we examined whether ASC-seeded hydrogels were able to modulate the recruitment and/or functionality of endogenous progenitor cells. Employing a parabiosis model and fluorescence-activated cell sorting analysis, we demonstrate that application of ASC-seeded hydrogels to wounds, when compared with injected ASCs or a noncell control, increased the recruitment of provascular circulating bone marrow-derived mesenchymal progenitor cells (BM-MPCs). BM-MPCs comprised 23.0% of recruited circulating progenitor cells in wounds treated with ASC-seeded hydrogels versus 8.4% and 2.1% in those treated with controls, p < 0.05. Exploring the potential for functional modulation of BM-MPCs, we demonstrate a statistically significant increase in BM-MPC migration, proliferation, and tubulization when exposed to hydrogel-seeded ASC-conditioned medium versus control ASC-conditioned medium (73.8% vs. 51.4% scratch assay closure; 9.1% vs. 1.4% proliferation rate; 10.2 vs. 5.5 tubules/HPF; p < 0.05 for all assays). BM-MPC expression of genes related to cell stemness and angiogenesis was also significantly increased following exposure to hydrogel-seeded ASC-conditioned medium (p < 0.05). These data suggest that ASC-seeded hydrogels improve both progenitor cell recruitment and functionality to effect greater neovascularization.
authors.affiliation: 1 Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Revanth
authors.initials: R
authors.lastname: Kosaraju
authors.affiliation: 1 Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rennert
authors.affiliation: 1 Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Zeshaan N
authors.initials: ZN
authors.lastname: Maan
authors.affiliation: 1 Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Dominik
authors.initials: D
authors.lastname: Duscher
authors.affiliation: 1 Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Janos
authors.initials: J
authors.lastname: Barrera
authors.affiliation: 1 Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Whittam
authors.affiliation: 1 Department of Surgery, Stanford University School of Medicine , Stanford, California.|2 Program in Biomedical Informatics, Stanford University School of Medicine , Stanford, California.
authors.forename: Michael
authors.initials: M
authors.lastname: Januszyk
authors.affiliation: 3 Biomaterials and Advanced Drug Delivery Center, Stanford University , Stanford, California.
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Rajadas
authors.affiliation: 1 Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Melanie
authors.initials: M
authors.lastname: Rodrigues
authors.affiliation: 1 Department of Surgery, Stanford University School of Medicine , Stanford, California.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Gurtner
mesh_terms: D000273:Adipose Tissue; D000818:Animals; D020100:Hydrogels / Q000737:chemistry*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic; D014947:Wounds and Injuries / Q000378:metabolism*
chemical_list: D020100:Hydrogels