**2.2. Use of placental mesenchymal stem/stromal cells in cancer**

axis (CXCR4-SDF1) is the main pathway mediating migration of MSC toward injured tissues. Since it has been shown that chemokine receptor type 4 (CXCR4) is greatly induced in PMSC by hypoxia, a high chemotactic response of PMSC to the ischemic microenvironment of the infarcted heart is expected [50]. Intravenous injection of PMSC in a rat model of infarct showed a sustained cardiac function over 32 weeks from injury [51]. Preconditioning PMSC by hyaluronan mixed ester of butyric and retinoic acid (HBR) potentiates their reparative capacity. Transplantation of preconditioned PMSC in pigs produced a significant reduction in scar size, higher myocardial perfusion and glucose uptake, enhanced capillary density, and decreased fibrous tissue [52]. The paracrine potential of conditioned medium (CM) of PMSC has also been evaluated. Injection of PMSC-CM limited infarct size and cardiomyocyte apoptosis, while promoting capillary density in the infarct border area in a rat model of

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

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

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

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].

CLI as blood capillaries cannot be corrected, and restenosis of vessels is produced.

ischemia/reperfusion [53].

234 Stromal Cells - Structure, Function, and Therapeutic Implications

*2.1.2. Critical limb ischemia*

effect for maximal blood flow recovery [57].

window for effective treatment.

*2.1.3. Stroke*

Cancer is one of the main problems in public health worldwide. Despite great progresses having been made in understanding the molecular basis of cancer, and the rapid advances in diagnosis, the efficacy of current treatment strategies is limited and mortality is still high. Stem cell-based treatments have been extensively explored for their possible potential to treat various cancers. Tumor microenvironment resembles a wound environment as tumors are considered as unhealed wounds [60]. Inflammatory and wound microenvironments induce migration of PMSC [36, 61]. Due to the characteristic of placenta-derived MSC, these cells represent an important tool for their use in anticancer therapies. First, PMSC can migrate and engraft into the tumor site and directly affect tumor biology through paracrine signaling. Second, PMSC could be used for the specific delivery of drugs to tumors thus reducing the doses administered and the side effects. Third, PMSC can also be genetically modified to give a stable expression of antitumor factors specifically in the tumor.

Placenta-derived MSC have an intrinsic tropism for sites of injury regardless of tissue or organ. Furthermore, it has been shown that PMSC and CM from PMSC are able to inhibit the proliferation of several tumor cell lines [62]. Moreover, PMSC have an antitumor effect in vivo, inhibiting tumor progression when were intravenously injected in a rat model of mammary cancer [12]. Similarly, PMSC showed antitumor effects in vivo when previously expanded in the presence of tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) [63] and when engineered to deliver growth factors to the tumor site, such as, pigment epitheliumderived factor [64], or endostatin [65].
