Autologous peripheral blood endothelial progenitor cells as a potential therapy for diabetic critical limb ischemia
Lyons, Caomhán
Lyons, Caomhán
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Publication Date
2023-10-20
Type
Thesis
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Abstract
[No abstract]
Diabetes mellitus (DM) results from impaired insulin secretion and/or insulin resistance and leads to heterogeneous clinical phenotypes. DM results in microvascular and macrovascular complications. One macrovascular complication which patients with DM have an increased risk of developing is critical limb ischaemia (CLI) which is a severe condition that can result in rest-pain, ulcer formation, and potentially limb amputation with high associated mortality. A novel therapy is needed to improve limb survival and reduce the mortality rate in patients with CLI. Endothelial-colony-forming cells (ECFCs) are a population of progenitor cells which have demonstrated promising angiogenic potential both in vitro and in vivo. It has been hypothesized that ECFCs may be a potential cell therapy option to promote revascularisation in patients with DM-CLI. While an allogeneic ECFC therapy approach would offer the potential of an ‘off the shelf’ therapeutic product, to date little research has been carried out on umbilical cord-ECFCs in diabetic models, and patients receiving allogeneic cell transplantation would require immunosuppression. Alternatively, an autologous cell therapy using peripheral blood-ECFCs would allow the development of a personalised therapeutic approach to CLI; however several studies have shown that ECFCs from diseased patients display a disease related dysfunction both in vitro and in vivo. A disease related dysfunction has also been shown in both ECFCs from patients with DM and in non-DM patients with ischaemic conditions compared to ECFCs from healthy donors. Many different groups have modified autologous diabetic ECFCs to improve their function using a variety of methods including pre-treatment with different factors or with genetic modification. While the in vitro and in vivo data from the literature is promising, no ECFC therapy has proceeded to clinical trials to date, indicating that more research is needed for a potential ECFC therapy in the future to treat DM-CLI. In addition, there have been no reports describing ECFC biology in patients with DM and CLI. This thesis investigates the suitability of ECFCs from patients with DM and CLI as an autologous therapy.
Diabetes mellitus (DM) results from impaired insulin secretion and/or insulin resistance and leads to heterogeneous clinical phenotypes. DM results in microvascular and macrovascular complications. One macrovascular complication which patients with DM have an increased risk of developing is critical limb ischaemia (CLI) which is a severe condition that can result in rest-pain, ulcer formation, and potentially limb amputation with high associated mortality. A novel therapy is needed to improve limb survival and reduce the mortality rate in patients with CLI. Endothelial-colony-forming cells (ECFCs) are a population of progenitor cells which have demonstrated promising angiogenic potential both in vitro and in vivo. It has been hypothesized that ECFCs may be a potential cell therapy option to promote revascularisation in patients with DM-CLI. While an allogeneic ECFC therapy approach would offer the potential of an ‘off the shelf’ therapeutic product, to date little research has been carried out on umbilical cord-ECFCs in diabetic models, and patients receiving allogeneic cell transplantation would require immunosuppression. Alternatively, an autologous cell therapy using peripheral blood-ECFCs would allow the development of a personalised therapeutic approach to CLI; however several studies have shown that ECFCs from diseased patients display a disease related dysfunction both in vitro and in vivo. A disease related dysfunction has also been shown in both ECFCs from patients with DM and in non-DM patients with ischaemic conditions compared to ECFCs from healthy donors. Many different groups have modified autologous diabetic ECFCs to improve their function using a variety of methods including pre-treatment with different factors or with genetic modification. While the in vitro and in vivo data from the literature is promising, no ECFC therapy has proceeded to clinical trials to date, indicating that more research is needed for a potential ECFC therapy in the future to treat DM-CLI. In addition, there have been no reports describing ECFC biology in patients with DM and CLI. This thesis investigates the suitability of ECFCs from patients with DM and CLI as an autologous therapy.
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Publisher
NUI Galway