Hypoxia preconditioned mesenchymal stem cells improve vascular and skeletal muscle fiber regeneration after ischemia through a Wnt4-dependent pathway.
Mesenchymal stem cells (MSC) are multipotent postnatal stem cells, involved in the treatment of ischemic vascular diseases. We investigate the ability of MSC, exposed to short-term hypoxic conditions, to participate in vascular and tissue regeneration in an in vivo model of hindlimb ischemia. Transplantation of hypoxic preconditioned murine MSC (HypMSC) enhanced skeletal muscle regeneration at day 7, improved blood flow and vascular formation compared to injected nonpreconditioned MSC (NormMSC). These observed effects were correlated with an increase in HypMSC engraftment and a putative role in necrotic skeletal muscle fiber clearance. Moreover, HypMSC transplantation resulted in a large increase in Wnt4 (wingless-related MMTV integration site 4) expression and we demonstrate its functional significance on MSC proliferation and migration, endothelial cell (EC) migration, as well as myoblast differentiation. Furthermore, suppression of Wnt4 expression in HypMSC, abrogated the hypoxia-induced vascular regenerative properties of these cells in the mouse hindlimb ischemia model. Our data suggest that hypoxic preconditioning plays a critical role in the functional capabilities of MSC, shifting MSC location in situ to enhance ischemic tissue recovery, facilitating vascular cell mobilization, and skeletal muscle fiber regeneration via a paracrine Wnt-dependent mechanism.
Leroux
Lionel
L
Inserm U828, Université Victor Ségalen, Pessac, France.
Descamps
Betty
B
Tojais
Nancy F
NF
Séguy
Benjamin
B
Oses
Pierre
P
Moreau
Catherine
C
Daret
Danièle
D
Ivanovic
Zoran
Z
Boiron
Jean-Michel
JM
Lamazière
Jean-Marie D
JM
Dufourcq
Pascale
P
Couffinhal
Thierry
T
Duplàa
Cécile
C
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006614:Hindlimb / Q000378:metabolism* / Q000473:pathology*; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060528:Wnt4 Protein
D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse