Thrombin-cleaved osteopontin regulates hemopoietic stem and progenitor cell functions through interactions with alpha9beta1 and alpha4beta1 integrins.
Osteopontin (OPN), a multifunctional acidic glycoprotein, expressed by osteoblasts within the endosteal region of the bone marrow (BM) suppresses the proliferation of hemopoietic stem and progenitor cells and also regulates their lodgment within the BM after transplantation. Herein we demonstrate that OPN cleavage fragments are the most abundant forms of this protein within the BM. Studies aimed to determine how hemopoietic stem cells (HSCs) interact with OPN revealed for the first time that murine and human HSCs express alpha(9)beta(1) integrin. The N-terminal thrombin cleavage fragment of OPN through its binding to the alpha(9)beta(1) and alpha(4)beta(1) integrins plays a key role in the attraction, retention, regulation, and release of hemopoietic stem and progenitor cells to, in, and from their BM niche. Thrombin-cleaved OPN (trOPN) acts as a chemoattractant for stem and progenitor cells, mediating their migration in a manner that involves interaction with alpha(9)beta(1) and alpha(4)beta(1) integrins. In addition, in the absence of OPN, there is an increased number of white blood cells and, specifically, stem and progenitor cells in the peripheral circulation.
Grassinger
Jochen
J
Australian Stem Cell Centre, Clayton, Australia.
Haylock
David N
DN
Storan
Melonie J
MJ
Haines
Gemma O
GO
Williams
Brenda
B
Whitty
Genevieve A
GA
Vinson
Andrew R
AR
Be
Cheang Ly
CL
Li
Songhui
S
Sørensen
Esben S
ES
Tam
Patrick P L
PP
Denhardt
David T
DT
Sheppard
Dean
D
Choong
Peter F
PF
Nilsson
Susan K
SK
D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002460:Cell Line; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D017931:DNA Primers / Q000235:genetics; D005312:Fetal Blood / Q000166:cytology; D015870:Gene Expression; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000378:metabolism*; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053495:Osteopontin / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism
D017931:DNA Primers; D039041:Integrin alpha4beta1; D016023:Integrins; D011994:Recombinant Proteins; C506896:Spp1 protein, mouse; C113256:integrin alpha 9 beta 1; D053495:Osteopontin; D016179:Granulocyte Colony-Stimulating Factor; D013917:Thrombin