Cord Lining Mesenchymal Stem Cells Have a Modest Positive Effect on Angiogenesis in Hindlimb Ischemia

Abstract

Purpose: We investigated the use of human Cord Lining Mesenchymal Stem Cells (CL-MSCs) (US Patent number 9,737,568), in a rabbit hindlimb ischemia model, and evaluated their potential in stimulating neovascularization. Allogenic human CL- MSCs could potentially be used to treat patients with lower limb ischemia and non-healing wounds.Methods: Twenty rabbits were divided into two separate groups. We created a hindlimb ischemia model surgically. At 21 and 49 days post-operatively, animals in the treatment group were injected with CL-MSCs (500,000 cells per 0.2 ml on each site) at 10 different sites (Quadriceps- 4 sites, Hamstrings- 4 sites and Calf-−2 sites) in the hindlimb muscles. The control group received only saline injection to the corresponding sites at the same time point as the treatment group. We then evaluated the effects of treatment on neovascularization by angiography, laser doppler perfusion imaging, as well as by histology. We evaluated the tissue samples for any signs of local immune reaction to the cell implantation. We also observed the rabbit clinically for any adverse effects after treatment.Results: We found a higher number of CD31 positive cells in the treatment group, with a greater number of capillaries found in the treated muscles. The Rectus Femoris demonstrated a median vessel count/muscle fiber of 0.121 for the treatment group, compared to 0.076 in the control group (median difference 0.04; 95% CI 0.001–0.11; p = 0.041). The Gastrocnemius demonstrated a median vessel count/muscle fiber of 0.175 for the treatment group, compared to 0.089 in the control group (median difference 0.087; 95% CI −0.006 to 0.234; p = 0.07). Blood perfusion quantification through Laser Doppler Perfusion Imaging (LDPI) also demonstrated a non-statistically significant increase in perfusion in favor of the treatment group. CL-MSCs demonstrated no toxicity associated morbidity and minimal local immune reaction to implantation.Conclusion: CL-MSCs have a positive effect on angiogenesis in a rabbit hindlimb ischemia model. This preliminary data is encouraging and paves the way for future large animal studies or for clinical trials.

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

“…In addition, the majority of prior studies have also used healthy rabbits, which have more rapid recovery from ischemia and responsiveness to angiogenic treatments. Overall, the improvement in revascularization observed in our research using a diseased rabbit model is comparable or superior to earlier studies that utilized healthy rabbit models of hindlimb ischemia to assess protein therapeutics 35–57 , cell therapies 58–62 , or gene therapy 55,63–75 . Consequently, our work supports that tmSCF nanodiscs would have potential as a therapeutic for ischemia, even in the context of therapeutic resistance as would be found in many human patients that have hyperlipidemia and diabetes.…”

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

“…In addition, the majority of prior studies have also used healthy rabbits, which have more rapid recovery from ischemia and responsiveness to angiogenic treatments. Overall, the improvement in revascularization observed in our research using a diseased rabbit model is comparable or superior to earlier studies that utilized healthy rabbit models of hindlimb ischemia to assess protein therapeutics 47 – 69 , cell therapies 70 – 74 , or gene therapies 67 , 75 – 87 . Consequently, this work supports that tmSCF nanodiscs would have potential as a therapeutic for ischemia, even in the context of therapeutic resistance as would be found in many human patients that have hyperlipidemia and diabetes.…”

Syndecan-4 Proteoliposomes Enhance Revascularization in a Rabbit Hind Limb Ischemia Model of Peripheral Ischemia

“…In general, the enhancement in revascularization seen in our study in this disease rabbit model is equivalent or greater than previous studies using healthy rabbit models of hindlimb ischemia to evaluate protein therapeutics, 7,8,22-42 gene therapy, 23,[43][44][45][46][47][48][49][50][51][52][53][54][55] or cell therapies. [56][57][58][59][60] Thus, our work supports that S4PL provides marked benefits for enhanced revascularization in comparison to growth factors alone and shows promise in addressing therapeutic resistance in pro-angiogenic treatments.…”