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B. Chaqour, M. B. Grant, A. Hasan, H. Liu, D. Lazarro; Priming Bone Marrow-Derived CD34+ Cells With the Matricellular Protein Cysteine-Rich Protein 61 (Cyr61/CCN1) Regulates Their Commitment to the Endothelial Cell Lineage Through the Integrin and Wnt Signaling Pathways. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2638.
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Development and remodeling of retinal blood vessels involves, at least in part, the recruitment and commitment of progenitor stem cells to vascular cell lineage. This complex process is imperfectly recapitulated in ischemic retinal diseases. The Cysteine-rich protein 61 (Cyr61/CCN1), is an inducible extracellular matrix protein with the potential of coordinating the execution of multiple angiogenic and vasculogenic programs involving vascular progenitor cells. This study examined the effects of Cyr61 on the differentiation of hematopoietic stem cells (HSCs) to endothelial cells.
The ability of recombinant (r) Cyr61 protein to induce cell adhesion, migration and differentiation of HSCs was examined using multiple in vitro assays. The functional significance of various integrin chain subtypes and their signaling pathways was examined using specific pharmacological inhibitors, neutralizing antibodies and pathway-specific microarrays.
Exposure of HSCs to rCyr61 induced their adhesion, migration, capillary-like structure formation and expression of specific endothelial cell markers. Cyr61 activated Pyk2, a focal adhesion kinase linked to integrin activation. Cyr61-induced cell adhesion was dependent on α6β1 while cell migration involved both α4 β1 and α6β1 integrin chains. Furthermore, Cyr61 activated the Wnt signaling cascade pathway as demonstrated by dephosphorylation of glycogen synthase kinase-3β and differential expression of multiple components of the Wnt pathway including Wnt proteins, their receptors and downstream targets such as Myc, fibronectin and cyclin D2. Inhibition of Wnt signaling reduced both cell adhesion and capillary-like structure formation upon cell exposure to rCyr61.
Priming with rCyr61 regulates HSC lineage commitment through stimulation of their vasculogenic potential , suggesting possible therapeutic utility of rCyr61 in retinal vascular diseases.
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