Objectives: Critical Limb Threatening Ischemia (CLTI) is a health care priority with a 50% increase in amputations from 2010 to 2018. Unlike other cell products that simply secrete pro-angiogenic growth factors Induced pluripotent stem cells (iPSC) derived mesodermal cells can differentiate into endothelial and smooth muscle cells and form functioning blood vessels in vivo . We discuss the effects of intramuscular injection of human iPSC mesodermal cells (VSC100) on limb perfusion and limb necrosis. Methods: IPSCs were produced using methods including Yamanaka factors (Broxmeyer H. et al [21393480}). iPSC cells were differentiated using sequential Activin A, BMP4, VEGF, and FGF2 to promote mesodermal and endothelial cell (EC) differentiation. Murine CLTI models were created via excision of the common femoral artery in male BALB-C Nude mice, aged 6-8 weeks. After creation of the CLTI model mice were randomized to 1x10 6 VSC100 cells labeled with td-tomato (red fluorescence) or vehicle control injected into the gastrocnemius and gracilis muscles (N=10/group) at 7-14 days postinduction of ischemia. Limb perfusion was measured with Laser Speckle Contrast Imaging (LSCI) up to Day 64, qualitative analysis of VSC100 differentiation into capillaries was assessed with immunohistochemical staining for Isolectin B4 and human CD31 and confocal microscopy to detect td-tomato. Degree of tissue loss of the index limb was quantified with established necrosis scores. Results: VSC100 treated mice showed a significant increase in limb perfusion compared to controls, average percent blood flow/contralateral limb ratios of 45% in treated groups compared to 25% in control (p < 0.001) at day 64 (Figure 1). Limb necrosis scores showed necrosis was statistically significantly reduced in iPSC treated versus vehicle control treated groups (Figure 2). Immunohistochemical analysis showed qualitative significant deposition of cells of interest in our CLTI models. Conclusions: iPSC derived VSC100 is a novel approach to treating CTLI as the cells can form functioning blood vessels in ischemic skeletal muscle, improve tissue perfusion, and mitigate tissue necrosis. These early results are being used for FDA applications for clinical trials utilizing iPSCs in CLTI patients.