Sphingosine kinase regulates the rate of endothelial progenitor cell differentiation.
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.
Bonder
Claudine S
CS
Division of Human Immunology, Hanson Institute, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia. claudine.bonder@imvs.sa.gov.au
Sun
Wai Y
WY
Matthews
Tyson
T
Cassano
Carlos
C
Li
Xiaochun
X
Ramshaw
Hayley S
HS
Pitson
Stuart M
SM
Lopez
Angel F
AF
Coates
P Toby
PT
Proia
Richard L
RL
Vadas
Mathew A
MA
Gamble
Jennifer R
JR
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
D017853:Phosphotransferases (Alcohol Group Acceptor); D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D000099157:Sphingosine Kinase; C115575:membrane-bound transcription factor peptidase, site 1