species accumulation in fibroblastic cells, and this activity underlies many CYR61-induced apoptosis and senescence. CYR61 is able to support cell adhesion, stimulate cell migration, promote growth factor-induced cell proliferation and differentiation in some cell types, promote apoptosis in synergy with TNF family cytokines, and induce cellular senescence in fibroblasts. Embryonic development During embryo development in mice, Cyr61 is highly expressed in the cardiovascular, skeletal, and neuronal systems. Cyr61 knockout mice are embryonic lethal due to defects in cardiac septal morphogenesis, deficient blood vessel formation in placenta, and compromised vascular integrity. In Xenopus laevis, Cyr61 is required for normal gastrulation and modulation of Wnt signaling. Clinical relevance CYR61 is highly expressed at sites of inflammation and wound repair, and is associated with diseases involving chronic inflammation and tissue injury. Wound healing and fibrosis In skin wound healing, CYR61 is highly expressed in the granulation tissue by myofibroblasts, which proliferate and rapidly synthesize ECM to maintain tissue integrity and to promote regeneration of parenchymal cells. However, excessive matrix deposition can lead to fibrosis, scarring, and loss of tissue function. In skin wounds, CYR61 accumulates in the granulation tissue as myofibroblasts proliferate, and eventually reaches a sufficiently high level to drive the myofibroblasts themselves into senescence, whereupon these cells cease to proliferate and express matrix-degrading enzymes. Thus, CYR61 limits synthesis and deposition of ECM by myofibroblasts, reducing the risk of fibrosis during wound healing. In addition to skin wound healing, CYR61 expression is elevated in remodeling cardiomyocytes after myocardial infarction, in vascular injury, and in the long bones during fracture repair. Blockade of CYR61 by antibodies inhibits bone fracture healing in mice. In the kidney, CYR61 is expressed in podocytes in normal adult and embryonic glomeruli, but expression is decreased in IgA nephropathy, diabetic nephropathy, and membranous nephropathy, particularly in diseased kidneys with severe mesangial expansion. CYR61 induction of cellular senescence in the kidney is a potential therapy to limit fibrosis. Inflammation CYR61 promotes the apoptotic functions of inflammatory cytokines such as TNFα, FasL, and TRAIL. It also reprograms macrophages towards M1 polarization through αMβ2-mediated activation of NF-κB. CYR61 is upregulated in patients with Crohn's disease and ulcerative colitis. CYR61 supports the patrolling behavior of murine resident Ly6Clow monocytes along the endothelial in the steady state and is required for their accumulation under viral-mimicking vascular inflammation. Arthritis CYR61 is highly expressed in collagen-induced arthritis in rodents, and inhibition of CCN1 expression correlates with