Adipose tissue-derived therapeutic cells for peripheral artery diseases: the fatty blessing

Peripheral arterial diseases (PAD) include non-occlusive arterial disease as well as all non-coronary arterial occlusive disease. In particular, lower extremity PAD is a major health problem that is however undertreated, and poorly understood by the medical community. Although it is frequently underor un-diagnosed, it has been estimated that 4.3% of the US population of 40 years and older has lower extremity PAD. A similar prevalence of PAD has been found in Western Europe, with population studies estimating the prevalence between 4–8%. A variety of risk factors have been identified for PAD. As such, preventable or treatable risk factors for PAD are generally thought to mirror other forms of cardiovascular disease and include cigarette smoking, type 2 diabetes, and clinically elevated levels of blood pressure and cholesterol, which are the main therapeutic targets in clinical and prevention guidelines. [1] Consistent with this, in a recent large prospective cohort study, the combination of the four clinical risk factors of smoking, hypertension, hypercholesterolemia, and type 2 diabetes was strongly and independently associated with risk of confirmed and clinically significant PAD. Duration of diabetes and hypercholesterolemia, severity of hypertension, and cumulative intensity of smoking, all demonstrated graded relationships with risk. [2] Intermittent claudication, described as pain in the muscles of the leg with ambulation, is the earliest and the most frequent presenting symptom in patients with lower extremity PAD. In the late stages of PAD defined as critical ischemia, diffuse multifocal steno-occlusive atherosclerotic lesions lead to hypoperfusion and ultimately to ischemic ulceration and gangrene of the affected territories. In this clinical setting, the restoration of perfusion by bypass surgery or angioplasty is considered as a first-line treatment. However, such treatment is possible in only 70% of cases. Furthermore, the durability of bypasses, particularly in cases of critical ischemia, is poor, and is no more than 50–70% three years after surgery. No other treatment has proved effective in this context so far, and major amputation is required in more than a third of these patients. Patients with PAD also display high risk of morbidity, including stroke and myocardial infarction, and the mortality rate reaches 50% within 6–10 years following the diagnosis. Current treatment is based on local care of trophic problems, possibly combined with systemic antibiotic treatment. Such ultimate failure of medical treatment and surgical revascularization procedures antecede the elaboration of subsidiary therapies for PAD. In particular, multiple different therapeutic cell-based strategies have been developed to promote vascular regeneration/remodeling and subsequently improve tissue perfusion in the affected territories. The majority of them used autologous adult cells and mainly applied total bone marrow-derived mononuclear cells, bone marrow or peripheral blood-derived marker selected cells and achieved encouraging results in animal experiments, often leading to their rapid proceeding to clinical testing. [3]