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Brahim Chaqour, Maria B. Grant, Adeel Hasan, Nataliya Pokeza, Lynn Shaw, Douglas Lazzaro; The Matricellular Protein Cysteine-Rich Protein 61 (CCN1/Cyr61) Enhances Hematopoietic Stem Cell-Mediated Normalization of the Retinal Vasculature After Oxygen-Induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3172.
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Circulating hematopoietic stem cells (HSCs) can function as blood vessel progenitors during vessel remodeling/repair and contribute to the stability and viability of the vasculature. The chemical signals that promote vascular regeneration/normalization following ischemic injury remain largely unknown. CCN1 protein also known as cysteine-rich protein 61 is a dynamically expressed, matricellular protein required for proper angiogenesis and vasculogenesis during development. This study examined the angiogenic potential of Cyr61-primed HSCs in the mouse model of oxygen-induced retinopathy (OIR).
Murine bone marrow-derived CD34+ hematopoietic stem cells (HSCs) were transduced with a lentivirus (Lnv) vector (10 moi) expressing either CCN1 or control luciferase (Luc) gene. Cells (~1 x 105) were injected into the vitreous of neonatal mice at P7 and pups were then placed in 72% O2 for 5 days. Vascular obliteration, retinal vascularization and preretinal neovascular tuft formation were quantified at day 17.
Greater than 30% of the retinal surface remained avascular when HSCs transduced with Lnv-Luc were injected while less than 15% of the retinal surface was vaso-obliterated when Lnv-CCN1-transduced HSCs were used (p<0.05). Injection of Lnv-CCN1-transduced HSCs significantly reduced preretinal neovascular tufts compared to eyes transplanted with Lnv-Luc-transduced HSCs (p<0.01). Fluorescently labeled, Lnv-CCN1-transduced HSCs localized within the retinal vessel wall of medium and small size vessels.
CCN1-primed HSCs enhance physiological adaptation of the retinal vasculature to hyperoxia and reduced pathological neovascularization following ischemia. This suggests a possible therapeutic utility for CCN1-primed HSCs in ischemic retinopathy.
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