Transmembrane stem factor nanodiscs enhanced revascularization in a hind limb ischemia model in diabetic, hyperlipidemic rabbits

Abstract

Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. To advance this therapeutic towards clinical application, we tested this therapy in an advanced model of hindlimb ischemia in rabbits with hyperlipidemia and diabetes. This model has therapeutic resistance to angiogenic therapies and maintains long term deficits in recovery from ischemic injury. We treated rabbits with local treatment with tmSCF nanodiscs or control solution delivered locally from an alginate gel delivered into the ischemic limb of the rabbits. After eight weeks, we found significantly higher vascularity in the tmSCF nanodisc-treated group in comparison to alginate treated control as quantified through angiography. Histological analysis also showed a significantly higher number of small and large blood vessels in the ischemic muscles of the tmSCF nanodisc treated group. Importantly, we did not observe inflammation or mast cell activation in the rabbits. Overall, this study supports the therapeutic potential of tmSCF nanodiscs for treating peripheral ischemia.

Unraveling the genetic basis of the causal association between inflammatory cytokines and osteonecrosis

“…Interestingly, however, the positive effects of SCF on osteogenesis, possibly through the c-Kit-Akt signaling pathway, have been recognized in recent years, which may also suggest that SCF may have beneficial effects on osteonecrosis repair ( 64 , 65 ). Additionally, studies have shown that SCF can stimulate cell migration and proliferation, promote blood vessel formation and maturation, and play an important role in angiogenesis and tissue engineering, which may be a potential therapeutic target for osteonecrosis ( 66 , 67 ). While only a limited number of clinical observational studies or meta-analyses have investigated the correlation between SCF and osteonecrosis or drug-induced osteonecrosis, our current MR analysis presents compelling evidence suggesting that elevated levels of circulating SCF are indeed associated with an increased risk of osteonecrosis.…”