*2.1.2. Critical limb ischemia*

Critical limb ischemia (CLI) is the advanced stage of peripheral artery disease (PAD) with progressive stenosis, and ultimately the obstruction of peripheral arteries. The consequences of the markedly reduced blood flow to the lower limbs are pain at rest, nonhealing ulcers, and gangrene. The risk factors of PAD are advanced age, hyperlipidemia, hypertension, and mainly diabetes. Unfortunately, amputation, in many cases, is the only therapeutic option for CLI as blood capillaries cannot be corrected, and restenosis of vessels is produced.

Preclinical studies have reported benefits of cell therapy in neovascularization in several mouse models of hindlimb ischemia. PMSC have demonstrated pro-angiogenic effects when intramuscularly injected into the ischemic region of the affected limb, improving blood flow and promoting new vessel formation [54–56]. Similar results have been described in a diabetic nude rat model [57]. Moreover, CM from the PMSC also had pro-angiogenic action in a mouse hindlimb ischemic model, comparable to the PMSC transplanted group in the same study, revealing that PMSC action resulted primarily from a paracrine action of the angiogenic factors released from the PMSC [55]. However, in another study, cells were more efficacious than cell lysate in rescuing blood flow, probably indicating the importance of prolonged paracrine effect for maximal blood flow recovery [57].

#### *2.1.3. Stroke*

Stroke is an acute focal injury of the central nervous system (CNS) by a vascular cause, including cerebral infarction, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH), and is a major cause of disability and death worldwide. Thrombolysis is the most commonly used therapeutic approach although most patients fall outside of the clinical time window for effective treatment.

Experimental data show that stem cell therapy can limit neuronal degeneration and improve the functional outcome. The neuroprotective action of PMSC has been demonstrated in a rat model of stroke. Intravenous administration of PMSC, 4 hours after the injury, resulted in a significant improvement of functional outcome and significant decrease of lesion volume, correlating with increased vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and brain-derived neurotrophic factor (BDNF) levels in the ischemic brain compared to controls [58].
