Transmembrane stem cell factor protein therapeutics enhance revascularization in ischemia without mast cell activation

Abstract

Stem cell factor (SCF) is a cytokine that regulates hematopoiesis and other biological processes. While clinical treatments using SCF would be highly beneficial, these have been limited by toxicity related to mast cell activation. Transmembrane SCF (tmSCF) has differential activity from soluble SCF and has not been explored as a therapeutic agent. We created novel therapeutics using tmSCF embedded in proteoliposomes or lipid nanodiscs. Mouse models of anaphylaxis and ischemia revealed the tmSCF-based therapies did not activate mast cells and improved the revascularization in the ischemic hind limb. Proteoliposomal tmSCF preferentially acted on endothelial cells to induce angiogenesis while tmSCF nanodiscs had greater activity in inducing stem cell mobilization and recruitment to the site of injury. The type of lipid nanocarrier used altered the relative cellular uptake pathways and signaling in a cell type dependent manner. Overall, we found that tmSCF-based therapies can provide therapeutic benefits without off target effects.

Transmembrane Stem Factor Nanodiscs Enhanced Revascularization in a Hind Limb Ischemia Model in Diabetic, Hyperlipidemic Rabbits

“…The findings are particularly significant given the rabbit model’s resistance to angiogenesis and longer-term ischemia 28,29 . Finally, we did not observe any signs of mast cell activation on histological analysis, consistent with our prior studies in mice 27 .…”

“…Managing ischemia in diabetic individuals has presented continuing challenges in the clinical setting, particularly for those undergoing bypass operations or percutaneous procedures 30,31 where diabetic patients have worse outcomes and reduced benefits from therapy and interventions. Our previous work demonstrated that tmSCF nanodiscs enhance revascularization in healthy and diabetic mice 32 . In this work, we evaluated the efficacy of tmSCF embedded in nanodiscs for therapeutic angiogenesis using an optimized rabbit model of hindlimb ischemia with diabetes and hyperlipidemia 28,29 .…”

“…Administering SCF results in mast cell activation and anaphylaxis in both animal studies and clinical trials, significantly restricts its potential for therapeutic use [22][23][24][25][26] . We recently found that tmSCF delivered in proteoliposomes or lipid nanodiscs was effective in inducing revascularization of ischemic limbs in diabetic and wild type mice but did not lead to mast cell activation 27 . Thus, tmSCF may provide benefits of soluble SCF without the toxic side effects that limited its usefulness as a therapeutic.…”

Novel Angiogenesis Role of GLP-1(32–36) to Rescue Diabetic Ischemic Lower Limbs via GLP-1R–Dependent Glycolysis in Mice

“…We also show that GLP-1 (32)(33)(34)(35)(36) improved mitochondrial dynamics and rescued glycolysis mediated by PFKFB3 (6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase 3). Our findings provide novel insights into the mechanisms underlying the beneficial effects of GLP-1 (32)(33)(34)(35)(36) on diabetic PAD and highlight its potential therapeutic value for nondiabetic patients due to its angiogenic effect independent of insulin regulation.…”

Transmembrane Stem Factor Nanodiscs Enhanced Revascularization in a Hind Limb Ischemia Model in Diabetic, Hyperlipidemic Rabbits

“…Managing ischemia in diabetic individuals has presented continuing challenges in the clinical setting, particularly for those undergoing bypass operations or percutaneous procedures 30,31 where diabetic patients have worse outcomes and reduced bene ts from therapy and interventions. Our previous work demonstrated that tmSCF nanodiscs enhance revascularization in healthy and diabetic mice 32 . In this work, we evaluated the e cacy of tmSCF embedded in nanodiscs for therapeutic angiogenesis using an optimized rabbit model of hindlimb ischemia with diabetes and hyperlipidemia 28,29 .…”