Role of Cell Therapy for Patients with Chronic Critical Limb Ischemia to Prevent Amputation

Editorial

bone marrow mononuclear cells (BM-MNC) implantation (n=26) had 95% major amputation free survival (MAFS) after 4 years, while it was only 6% in control (n=16) Buerger’s patients (P<0.0001) [1, 2, 3, 4]. Among the atherosclerotic PAD patients with BM-MNC implantation (n=25), MAFS after 4 years were 48% whereas no control (n=30) patients (0%) with atherosclerotic PAD could have 4 year MAFS (P<0.0001).1In TACT(Therapeutic Angiogenesis by Cell Transplantation) trial, patients with chronic limb ischemia (Fontaine stage III and IV, PAD due to ASO, n = 74 and Buerger’s n = 41), three-year amputation-free rate was 60% in ASO and 91% in patients with Buerger’s. Our study and study done by others reveal that autologous BM-MNC implantation improves endothelial function in patients with chronic CLI patients along with improvement of limb ischemic symptoms and findings of angiography [2, 3]. BM-MNC implantation increases collateral vessel formation and improves ischemic symptoms in patients with CLI. Paracrine effect of bone marrow cells and/ or role of endothelial progenitor cells contained in bone marrow cells are considered the reason of healing. It is evident that patients with Buerger’s disease have superior outcome compared to the patients with ASO. Our study demonstrates that patients with Buerger’s have better endothelial progenitor cell functionality compared to that of ASO [1]. Among patients with ASO, those having severe ASO and/or several comorbidities like end stage renal failure and diabetes mellitus have poorer outcome. In Japan, BM-MNC implantation is now carried out under advanced insurance program. However, not all the patients with ASO can get benefit from the usage of BM- MNC implantation. Still a significant proportion of patients with chronic CLI need to undergo major amputation. And patients with ischaemic limb ulcers reaching until bone need at least minor amputation. These scenarios necessitate the development of further strategies for those patients. One of the solutions could be usage of cells with higher regenerative potential. Although embryonic stem (ES) cells have pluripotent characteristics and can differentiate to various tissue types, ethical issues could be a hurdle to clinical use and inherent allogenicity of these cells will require administering long-term immune suppression in clinical subjects. There is also the risk of teratoma formation. Generation of patient-specific induced pluripotent stem (iPS) cells to overcome allogenicity is time-consuming, expensive and might be meaningless for urgent usage [5, 6]. Umbilical Cord blood (UCB) cells also have some degree of pluripotentiality and can differentiate into various tissue types like the ES cells. Both in vitro and in vivo experiments proved that cord blood stem cells have the capacity to produce neural, epithelial, endothelial and hematopoietic tissues. It has been used for around 25 years to treat hematological disorders but no malignant transformation has been seen, except for instances where an abnormal gene is already present at the time of cord blood collection. Therefore, the pluripotency, ethical clarity and proven safety of UCB cells raised some optimism that it could be useful in critical limb ischaemia [6]. A phase 1 study done by Yang SS et.al, demonstrates that intramuscular human UCB driven mesenchymal stem cells (MSC) injection is a safe and well tolerated treatment for patients with chronic CLI due to ASO and Buerger’s [7]. Exploration of Bone marrow derived mesenchymal stem cells (BM-MSC) might be another alternative for BM- MNC in chronic CLI patients. A prospective, double blind randomized placebo controlled multi-center study done by Gupta, et al. finds that BM-MSCs are safe when injected intra-muscularly at a dose of 2 million cells/kg body weight. Study was conducted among patients with chronic CLI not suitable for or had failed revascularization treatment and having Rutherford classification in category II-4, III-5, or III-6 with infra-inguinal arterial occlusive disease. Twenty patients received allogeneic BM-MSCs (n=10) or placebo (Plasma Lyte A, n=10) at the gastrocnemius muscle of the ischemic limb. Patients receiving BM-MSC showed significantly increased ankle – brachial pressure index (ABPI) and ankle pressure at 24 weeks [8].

Adipose-derived regenerative cells (ADRCs) are an encouraging alternative source of autologous somatic stem cells for regeneration of damaged tissue. Study done by Kondo K, et al. shows promising outcome and no major safety issues after usage of ADRCs for CLI patients although number of cases were six only [9]. In conclusion, autologous BM-MNC is one of the safe options to treat patients with chronic CLI. Usages of BM- MSC, UCB cells or ADRCs need ex-vivo manipulation. Therefore, safety concerns are needed to be addressed properly and further studies with large numbers of patients are needed to confirm initial outcome.