*2.1.1. Myocardial infarction*

**1.5. Placenta-derived mesenchymal stromal cells**

232 Stromal Cells - Structure, Function, and Therapeutic Implications

anticancer agents to the tumor site.

Mesenchymal stromal cells (MSC) can be isolated from virtually all adult tissues in the body, although not always in large quantities. They are thought to be a precursor cell population capable of reconstituting all the cellular elements that comprise the supportive stromal tissue in each organ [34]. First described in bone marrow as a subset of non-hematopoietic cells [35], they have become the paradigm cell in regenerative medicine. MSC are the most widely studied cell type in both preclinical and clinical trials. The advantages of MSC include ease of isolation and subsequent maintenance in culture, high expansion capacity, high plasticity, and tissue repair activity. The restorative activity of MSC is not necessarily by the replacement of dead or damaged cells, but also, by paracrine actions that mediate immune-regulation and promote cell growth and/or differentiation (**Figure 2**). Besides, MSC do not form teratomas after transplantation, ensuring safety to the host and, their low immunogenicity makes them suitable for allogeneic transplantation. Furthermore, these cells have the ability to migrate to inflammatory microenvironments [36] and tumors [12, 37], where they play an active role inducing many processes, such as angiogenesis and wound healing, mainly in a paracrine manner [38]. This feature provides an important therapeutic advantage to MSC since they can be injected via systemic infusion and can be used as vehicles for the delivery of drugs such as

The use of placenta as a source of MSC has several advantages with respect to other adult MSC. Besides the ease of extraction of MSC from the placenta without invasive methods, the isolated MSC represent a more homogeneous and primitive population [9, 39]. The last feature is associated with a higher proliferative rate in culture compared to bone marrow MSC [40]. This fact makes it possible to achieve a greater number of cells in fewer passages

**Figure 2.** PMSC mechanisms of action. PMSC can migrate, home, and differentiate into tissue specific cells to repair injured tissue, transport restorative genes and used as a cellular vehicles of therapeutic agents. PMSC also exert their

actions through paracrine effects and have immunomodulatory properties.

Myocardial infarction (MI) is a major cause of death and disability worldwide. MI occurs when there is an interruption in blood flow to the heart muscle followed by heart ischemia. Since regeneration of heart muscle is virtually absent, damaged myocardium after infarct is replaced by scar tissue leading to reduced cardiac function. PMSC transplantation is a promising strategy to restore cardiac function and reduce myocardial fibrosis in MI due to their angiogenic and immunosuppressive properties.

PMSC have the potential to differentiate into cardiomyocytes, and exhibit spontaneous beating under in vitro conditions suggesting that they can therapeutically act in the cardiac repair process [9, 48, 49]. Several groups have investigated the effects of PMSC when transplanted in animal models of MI. PMSC injected into rat hearts after the induction of a MI showed integration into cardiac tissues and in vivo transdifferentiation into cardiomyocytes [48]. The CXCR4 chemokine receptor and its ligand, stromal cell-derived factor (SDF-1) 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 ischemia/reperfusion [53].

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

a stable expression of antitumor factors specifically in the tumor.

drocytes [66], glial cells [67], and dopaminergic neurons [68].

antiapoptotic effects, could also alleviate these nonmotor symptoms.

derived factor [64], or endostatin [65].

*2.3.1. Parkinson's disease*

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

Human Placenta-Derived Mesenchymal Stromal Cells: A Review from Basic Research to Clinical Applications

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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 epithelium-

Neurodegeneration involves a progressive and irreversible loss of neurons. Alzheimer's, Parkinson's, and multiple sclerosis are some of the more studied neurodegenerative syndromes. The neuromuscular disorder amyotrophic lateral sclerosis (ALS) is a degenerative process caused by motor neuron loss. To date, there is no cure for these diseases. Cell therapy with stem cells arises as a therapeutic alternative based, either on the replacement of the lost neurons, or on a neuroprotective action through release of neurotrophic factors. PMSC are able to differentiate in vitro into several neural lineages, including neurons [9, 66], oligoden-

Parkinson's disease (PD) is a progressive neurodegenerative disease associated with a specific loss of dopaminergic neurons in the substantia nigra and depletion of dopamine levels in the striatum. The main therapeutic objective in PD is the recovery of dopaminergic neurotransmission in the striatum. Cellular replacement has been emerged as a suitable therapeutic strategy. First-trimester human PMSC differentiated to neural progenitors and transplanted into the striatum of a rat model of PD, underwent dopaminergic differentiation and showed an attenuation of the symptoms [69]. PD motor pathology is also accompanied by other disabilities, such as, mood disorders, constipation, and hyposmia. It is expected that besides the regenerative effects of PMSC, the secretion of trophic factors, their anti-inflammatory and

**2.3. Use of placental mesenchymal stem/stromal cells in neurological diseases**
