Co-culture of hematopoietic stem cells with mesenchymal stem cells increases VCAM-1-dependent migration of primitive hematopoietic stem cells

Abstract

Hematopoietic stem cells (HSC) lose their capacity for engraftment during ex vivo cytokine expansion. It has been shown that mesenchymal stem cells (MSC) improve HSC transplantability; however, the molecular mechanisms responsible for this effect have not yet been completely elucidated. This paper reports that expanding HSC in co-culture with MSC enhances a vascular cell adhesion molecule (VCAM-1)-dependent pro-migratory phenotype. MSC did not regulate the HSC expression of CD49d (VCAM-1 counter-receptor molecule), but did decrease the cytokine-induced HSC VCAM-1-mediated pro-adhesive phenotype. Co-culture with MSC reduced the expression of the inactive conformation of lymphocyte function-associated antigen (LFA-1) at the HSC uropod, and induced higher expression of an LFA-1 activation epitope. Interestingly, VCAM-1-dependent HSC migration was modulated by targeting this LFA-1 high affinity form, suggesting integrin cross-regulation. VCAM-1-mediated HSC transmigration appeared to favor the more primitive HSC immunophenotype. Our results suggested that co-culture with MSC improved VCAM-1-dependent migration of primitive HSC, which was affected in ex vivo cytokine-expanded HSCs by a mechanism involving LFA-1 modulation.