Dual stem cell therapy from adipose tissue facilitates arteriogenesis and limb preservation in experimental critical limb ischemia via direct vascular integration

Peripheral artery disease (PAD) is a progressive vascular disorder characterized by arterial narrowing and stiffening, most often in the lower limbs. In advanced stages, PAD can progress to critical limb ischemia (CLI) due to complete arterial occlusion. Limited revascularization options for CLI underscore the urgent need for novel and safe therapeutic strategies.Vascular multipotent stem cells (VMSCs) and adipose-derived stem cells (ADSCs) were isolated from adipose tissue, phenotypically characterized, and assessed for angiogenic potential in vitro . Their therapeutic efficacy was evaluated in a murine CLI model by intramuscular transplantation, followed by assessment of limb preservation, neovascularization, and cell integration into host tissue.VMSCs shared mesenchymal stem cell–like features with ADSCs but exhibited markedly higher proliferative capacity, enabling rapid expansion to clinically relevant numbers. VMSCs also demonstrated endothelial-like properties, including CD31, VE-cadherin, and CD141 expression, and formed capillary-like structures in vitro . In contrast, ADSCs displayed perivascular characteristics with α-SMA and Transgelin expression. Co-culture of VMSCs and ADSCs promoted the development of mature tubular networks in vitro . Combined cell transplantation markedly decreased limb loss and promoted both angiogenesis and arteriogenesis in ischemic tissue, with transplanted cells partially integrating into the host vasculature to form hybrid vascular structures.VMSCs and ADSCs exhibit complementary regenerative properties, sustained engraftment, and the ability to support large-vessel formation, highlighting their promise for stem cell–based vascular therapies.