Endothelial progenitor cells (EPCs)

Endothelial progenitor cells (EPCs) belong to an immature cell population that is capable of differentiating into mature endothelial cells. In adults, EPCs mainly reside in bone marrow (BM) and are more proliferative and migrative than terminally differentiated endothelial cells. EPCs can be clinically isolated as CD34þ or AC133þ mononuclear cells (MNCs) from adult BM or peripheral blood (PB) [64]. Tissue ischemia or systemic administration of G-CSF, GM-CSF, vascular endothelial growth factor, or estrogen enhances mobilization of EPCs from BM into PB, and the mobilized EPCs specifically home to sites of nascent neovascularization, thereby contributing to vascular repair.

Many studies have shown efficiency of autologous bone marrow cell injections into ischemic limbs [65]. In recent times, there is a trend towards usage of peripheral blood stem cells as alternate to BM stem cells. In a study by Moriya et al. [66] in 42 patients of TAO treated with peripheral blood mononuclear stem cells, improvement of ischemic symptoms was observed in 60% to 70% of the patients. The annual rate of major amputation was decreased markedly by treatment.

In a study by Kawamoto et al. [67] in 17 patients with TAO who were treated with intramuscular injection of G CSF mobilized CD34+ cells from peripheral blood. During the 12-week observation after cell therapy, the Wong-Baker FACES pain rating scale, transcutaneous partial oxygen pressure, total or pain-free walking distance, and ulcer size serially improved in all patients.

Cell therapies using bone marrow mononuclear cells (BM-MNCs) and peripheral blood mononuclear cells (PBMNCs) have effective outcomes in patients with peripheral artery disease and TAO. The adipose tissue is abundant in the human body and is consistently replenished. Therefore, this tissue is an ideal source of MSCs. It has been shown that adipose tissue derived MSCs (ATMSCs) have characteristics similar to those of bone marrow stromal cells (BMSCs) [68]. ATMSCs differentiate into endothelial cells and have a proangiogenic effect. In a study by Lee et al. [69] 15 patients with TAO were treated with intramuscular injections of ATMSCs; it was seen that clinical improvement occurred in 66.7% of patients. Five patients required minor amputation during followup, and all amputation sites healed completely. At 6 months, significant improvement was noted on pain rating scales and in claudication walking distance. Digital subtraction angiography before and 6 months after ATMSCs implantation showed formation of numerous vascular collateral networks across affected arteries. Further large-scale randomized trials are required to assess the long-term benefits of stem cell therapy.
9. Conclusion

TAO is a distinct form of systemic vasculitis of unknown etiology though strongly linked to cigarette smoking. Clinical features and angiography form the main basis of diagnosis. Abstinence from smoking is the only definitive treatment to prevent disease progression. Medical line of treatment with vasodilators, pentoxyfylline, and cilostazol may help improve pain-free walking distance but cannot prevent disease progression. Surgical treatment in form of revascularization, sympathectomy, Ilizarov, and omentopexy increases peripheral blood flow and decreases the rate of amputations. Newer therapy with prostaglandins, bosentan, and stem cell therapy has shown promising results. Early diagnosis and aggressive therapy can decrease patient symptoms and chances of major amputations.