title: An acellular matrix-bound ligand enhances the mobilization, recruitment and therapeutic effects of circulating progenitor cells in a hindlimb ischemia model.
abstract: Circulating progenitor cells home to and engraft to sites of ischemia, mediated in part by the adhesion molecule L-selectin; however, accumulation in tissues such as the heart is low. In this study, an acellular collagen-based matrix containing sialyl Lewis(X) (sLe(X)), which binds L-selectin, was developed in order to enhance the endogenous progenitor cell therapeutic response. Its effect on progenitor cells and angiogenesis were assessed in vitro and using a hindlimb ischemia model with rats. In culture, the sLe(X)-collagen matrix recruited more CD133(+)CD34(+)L-selectin(+) cells than collagen-only matrix, with adhesion mediated by L-selectin binding. Increased angiogenic/chemotactic cytokine production and improved resistance to apoptosis appeared in cells cultured on sLe(X)-collagen matrix. In vivo, mobilization of endogenous circulating progenitor cells was increased, and greater recruitment of these and systemically injected human peripheral blood CXCR4(+)L-selectin(+) cells to sLe(X)-collagen treated limbs was observed compared to collagen-only. This condition was associated with differences in angiogenic/chemotactic cytokine levels, with greater arteriole density and increased perfusion in sLe(X)-collagen treated hindlimbs. With these factors taken together, we demonstrated that an acellular matrix-bound ligand approach can enhance the mobilization, recruitment, and therapeutic effects of endogenous and/or transplanted progenitor cells, possibly through paracrine and antiapoptotic mechanisms, and could be used to improve cell-based regenerative therapies.
authors.affiliation: Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin St., Ottawa, ON, K1Y 4W7, Canada. esuuronen@ottawaheart.ca
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Suuronen
authors.forename: Pingchuan
authors.initials: P
authors.lastname: Zhang
authors.forename: Drew
authors.initials: D
authors.lastname: Kuraitis
authors.forename: Xudong
authors.initials: X
authors.lastname: Cao
authors.forename: Angela
authors.initials: A
authors.lastname: Melhuish
authors.forename: Daniel
authors.initials: D
authors.lastname: McKee
authors.forename: Fengfu
authors.initials: F
authors.lastname: Li
authors.forename: Thierry G
authors.initials: TG
authors.lastname: Mesana
authors.forename: John P
authors.initials: JP
authors.lastname: Veinot
authors.forename: Marc
authors.initials: M
authors.lastname: Ruel
mesh_terms: D000071916:AC133 Antigen; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology*; D064987:Cell- and Tissue-Based Therapy; D003094:Collagen / Q000737:chemistry / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D006023:Glycoproteins / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D007511:Ischemia / Q000628:therapy*; D019041:L-Selectin / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000276:immunology; D009844:Oligosaccharides / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000080506:Sialyl Lewis X Antigen; D013234:Stem Cells / Q000502:physiology*
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D016207:Cytokines; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D009844:Oligosaccharides; C000606023:PROM1 protein, human; D010455:Peptides; C000606025:Prom1 protein, rat; D000080506:Sialyl Lewis X Antigen; D019041:L-Selectin; D003094:Collagen