title: Sphingosine kinase regulates the rate of endothelial progenitor cell differentiation.
abstract: Circulating endothelial progenitor cells (EPCs) are incorporated into foci of neovascularization where they undergo differentiation to mature endothelial cells (ECs). We show here that the enzyme sphingosine kinase-1 (SK-1) regulates the rate and direction of EPC differentiation without effect on the hematopoietic compartment. EPCs have high levels of SK-1 activity, which diminishes with differentiation and is, at least partially, responsible for maintaining their EPC phenotype. EPCs from SK-1 knockout mice form more adherent EC units and acquire a mature EC phenotype more rapidly. Conversely, EPCs from mice overexpressing SK-1 in the EC compartment are retarded in their differentiation. Exogenous regulation of SK-1 levels in normal EPCs, by genetic and pharmacologic means, including the immunomodulating drug FTY720, recapitulates these effects on EC differentiation. SK-1 knockout mice have higher levels of circulating EPCs, an exaggerated response to erythropoietin-induced EPC mobilization, and, in a mouse model of kidney ischemia reperfusion injury, exhibit a recovery similar to that of ischemic mice administered exogenous EPCs. Thus, SK-1 is a critical player in EPC differentiation into EC pointing to the potential utility of SK-1 modifying agents in the specific manipulation of endothelial development and repair.
authors.affiliation: Division of Human Immunology, Hanson Institute, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia. claudine.bonder@imvs.sa.gov.au
authors.forename: Claudine S
authors.initials: CS
authors.lastname: Bonder
authors.forename: Wai Y
authors.initials: WY
authors.lastname: Sun
authors.forename: Tyson
authors.initials: T
authors.lastname: Matthews
authors.forename: Carlos
authors.initials: C
authors.lastname: Cassano
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Li
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Ramshaw
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pitson
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.forename: P Toby
authors.initials: PT
authors.lastname: Coates
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
authors.forename: Mathew A
authors.initials: MA
authors.lastname: Vadas
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Gamble
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D043484:Proprotein Convertases / Q000502:physiology; D012697:Serine Endopeptidases / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism / Q000502:physiology*; D000099157:Sphingosine Kinase
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D000099157:Sphingosine Kinase; C115575:membrane-bound transcription factor peptidase, site 1