Library - Critical limb ischemia

Front Biosci (Landmark Ed). 2014 Jan 1;19:768-76.

Application of adipose-derived stem cells in critical limb ischemia.

Zhi K1Gao Z1Bai J1Wu Y1Zhou S1Li M2Qu L1.

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1Department of Vascular and Endovascular Surgery Changzheng Hospital 415 Fengyang Road, Shanghai, China.

2Department of Interventional Radiology, Tenth People’s Hospital of Tongji University, 301 Yanchang Road, Shanghai,China, 200072.


Peripheral artery disease is growing in global prevalence. Its most severe form, critical limb ischemia (CLI), is associated with high rates of limb loss, morbidity, and mortality. Neovascularization is the cornerstone of limb preservation in CLI. In the field of regenerative medicine, basic research and preclinical studies have been conducted using mesenchymal stem cells (MSCs) from adult tissues, including bone marrow andadipose tissue, to overcome clinical shortcomings. Adipose-derived stem cells (ASCs) display stable growth and proliferation kinetics and can differentiate into osteogenic, chondrogenic, adipogenic, myogenic or neurogenic lineages. ASCs are readily available from autologous adiposetissue, and have significant potential for tissue repair under conditions of myocardial infarction, heart failure, hind limb ischemia, and inflammation. This review highlights some of the key reports underlining the potential of ASCs, particularly in diseases involving neovascularization.

Cytotherapy. 2014 Feb;16(2):245-57. doi: 10.1016/j.jcyt.2013.11.011.

Phase I trial: the use of autologous cultured adipose-derived stroma/stem cells to treat patients with non-revascularizable critical limb ischemia.

Bura A1Planat-Benard V2Bourin P3Silvestre JS4Gross F5Grolleau JL6Saint-Lebese B7Peyrafitte JA2Fleury S2Gadelorge M2Taurand M2Dupuis-Coronas S2Leobon B8Casteilla L9.

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1Service de médecine vasculaire, Pôle cardiovasculaire et métabolique, Centre hospitalo-universitaire de Toulouse, Toulouse, France; Université de Toulouse III, Paul Sabatier, Toulouse, France.



Non-revascularizable critical limb ischemia (CLI) is the most severe stage of peripheral arterial disease, with no therapeutic option. Extensive preclinical studies have demonstrated that adipose-derived stroma cell (ASC) transplantation strongly improves revascularization and tissue perfusion in ischemic limbs. This study, named ACellDREAM, is the first phase I trial to evaluate the feasibility and safety of intramuscular injections of autologous ASC in non-revascularizable CLI patients.


Seven patients were consecutively enrolled, on the basis of the following criteria: (i) lower-limb rest pain or ulcer; (ii) ankle systolic oxygen pressure <50 or 70 mm Hg for non-diabetic and diabetic patients, respectively, or first-toe systolic oxygen pressure <30 mm Hg or 50 mm Hg for non-diabetic and diabetic patients, respectively; (iii) not suitable for revascularization. ASCs from abdominal fat were grown for 2 weeks and were then characterized.


More than 200 million cells were obtained, with almost total homogeneity and no karyotype abnormality. The expressions of stemness markers Oct4 and Nanog were very low, whereas expression of telomerase was undetectable in human ASCs compared with human embryonicstem cells. ASCs (10(8)) were then intramuscularly injected into the ischemic leg of patients, with no complication, as judged by an independent committee. Trans-cutaneous oxygen pressure tended to increase in most patients. Ulcer evolution and wound healing showed improvement.


These data demonstrate the feasibility and safety of autologous ASC transplantation in patients with objectively proven CLI not suitable for revascularization. The improved wound healing also supports a putative functional efficiency.


ASC; CLI; adipose tissue; cell therapy; mesenchymal stromal cells

Circ J. 2012;76(7):1750-60. Epub 2012 Apr 12.

Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia: a pilot study.

Lee HC1An SGLee HWPark JSCha KSHong TJPark JHLee SYKim SPKim YDChung SWBae YCShin YBKim JIJung JS.

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1Division of Cardiology, Department of Internal Medicine, Pusan National University, Medical Research Institute, Pusan Medical University Hospital, Busan, Korea.



Treatment of critical limb ischemia (CLI) by bypass operation or percutaneous vascular intervention is occasionally difficult. The safety and efficacy of multiple intramuscular adipose tissue-derived mesenchymal stem cells (ATMSC) injections in CLI patients was determined in the study.


The study included 15 male CLI patients with ischemic resting pain in 1 limb with/without non-healing ulcers and necrotic foot. ATMSC were isolated from adipose tissue of thromboangiitis obliterans (TAO) patients (B-ATMSC), diabetes patients (D-ATMSC), and healthy donors (control ATMSC). In a colony-forming unit assay, the stromal vascular fraction of TAO and diabetic patients yielded lesser colonies than that of healthy donors. D-ATMSC showed lower proliferation abilitythan B-ATMSC and control ATMSC, but they showed similar angiogenic factor expression with control ATMSC and B-ATMSC. Multiple intramuscular ATMSC injections cause no complications during the follow-up period (mean follow-up time: 6 months). Clinical improvement occurred in 66.7% of patients. Five patients required minor amputation during follow-up, 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 ATMSC implantation showed formation of numerous vascular collateral networks across affected arteries.


Multiple intramuscular ATMSC injections might be a safe alternative to achieve therapeutic angiogenesis in patients with CLI who are refractory to other treatment modalities.