**2.6. Use of placental mesenchymal stem/stromal cells in intestinal inflammatory diseases**

Crohn's disease (CD) and ulcerative colitis (UC) are chronic conditions caused by a sustained inflammation of the intestinal epithelium that ends in tissue destruction throughout the gastrointestinal tract. It is believed that these disorders are the result of an abnormal host immune response to intraluminal antigens in genetically predisposed individuals. Several genetic variants of nucleotide-binding oligomerization domain 2 (NOD2) are associated with the development of Crohn's disease [86]. Both pathologies have a major impact on the quality of life and there is no curative treatment. Furthermore, many patients are not responsive to current therapy.

In bone regenerative medicine, the RKKP glass ceramic has been proposed as a biocompatible support for PMSC. RKKP exhibits a higher osteointegration rate compared to other ceramic materials mainly in osteopenic bone. Additionally, the biology of PMSC is not affected when grown over this support while maintaining their osteogenic potential [93] PMSC seeded over poly-L-lactic acid (PLLA) nanofibrous scaffolds and subjected to osteogenic conditions have

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Some systems have shown suitable behaviors as recipients of PMSC for cartilage regeneration. Collagen sponge allowed the formation of a cartilage-like tissue both, in vitro and in vivo, under chondrogenic-inducing conditions [95]. Similarly, PMSC embedded in alginate incorporating nanosized calcium-deficient hydroxyapatite (nCDHA) and/or a recombinant protein containing arginine-glycine-aspartate (RGD) and seeded over poly(D,L-lactide-co-glycolide)

The use of nanoparticles for gene/drug delivery can significantly contribute to the advance of regenerative medicine. The use of stem cells as carriers of NPs containing biologically active molecules (e.g., pro-survival, anti-inflammatory) or chemicals such as anticancer drugs is very promising. PMSC have been employed as a platform to load mesoporous silica nanoparticles. NP loading did not affect the chemotactic ability of PMSC toward tumors in vitro and in vivo. When carrying doxorubicin-loaded NP, PMSC promoted breast cancer cells death in a coculture system [97]. In a proof of concept, ultrasound-responsive NPs loaded with antitumor drugs were transported to tumor tissues by PMSC, and the cargo was released by NPs only

In vivo monitoring of cells, after transplant, is needed and NP-based probes are useful for this purpose. They offer the possibility of tracking the bio-distribution and engraftment of cells into the body with minimally invasive techniques. However these probes have to ensure minimal changes in cell phenotype [97]. PMSC have been efficiently labeled with albuminconjugated fluorescent nanodiamonds (FNDs) [99], with silica-coated magnetic nanoparticles incorporating rhodamine B isothiocyanate, MNPs@SiO2(RITC) [100], with rhodamine B labeled mesoporous silica nanoparticles [98] and with human serum albumin coated iron

oxide nanoparticles (HSA-IONPs) [101] without any detrimental effect.

**4. Therapeutic applications of placenta mesenchymal stem/stromal** 

Based on the benefits produced by transplanted PMSC in different animal models resembling human diseases, some clinical studies have been carried out and there are also an increasing number of ongoing clinical trials. The web pages http://www.clinicaltrialsregister.eu and http://www.clinicaltrial.gov offer up-to-date information on clinical trials giving current status. There are a good number of completed trials of which no results have yet been published. Other completed studies and clinical trials have published reports with the results obtained demonstrating the safety of the use of PMSC. In general, therapeutic benefits have been found. Intracoronary infusion of UC-MSC in MI patients resulted in safe and significantly improved myocardial viability and the perfusion within the infarcted area. Improvement in some

been successfully grafted in a rabbit model of sternal defect closure [94].

(PLGA) gave rise to cartilage formation [96].

after ultrasound application [98].

**cells (PMSC) in clinical trials**

Intraperitoneal administration of conditioned medium from PMSC ameliorated clinical parameters in a mouse model of dextran sulfate sodium (DSS)-induced colitis [87]. Intraperitoneal injection of PMSC also prevented the loss of body weight and decreased the mortality of mice. These benefits were greater when NOD2-activated PMSC were used [88].
