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Gonzalez P.L.,University of Los Andes, Chile | Carvajal C.,University of Los Andes, Chile | Cuenca J.,University of Los Andes, Chile | Alcayaga-Miranda F.,University of Los Andes, Chile | And 5 more authors.
Stem Cells Translational Medicine | Year: 2015

Mesenchymal stem cells (MSCs) of placental origin have become increasingly translational owing to their abundance and accessibility. MSCs of different origin share several features but also present biological differences that might point to distinct clinical properties. Hence, mixing fetal and maternal cells from the same placenta can lead to contradicting results. We analyzed the biological characteristics of haploidentical MSCs isolated from fetal sources, including the umbilical cord (UC-MSCs) and chorion (Ch-MSCs), compared with maternal decidua MSCs (Dc-MSCs). All MSCs were analyzed for general stem cell properties. In addition, immunosuppressive capacity was assessed by the inhibition of T-cell proliferation, and angiogenic potential was evaluated in a Matrigel transplantation assay. The comparison between haploidentical MSCs displayed several distinct features, including (a) marked differences in the expression of CD56, (b) a higher proliferative capacity for Dc-MSCs and UC-MSCs than for Ch-MSCs, (c) a diversity of mesodermal differentiation potential in favor of fetal MSCs, (d) a higher capacity for Ch-MSCs to inhibit T-cell proliferation, and (e) superior angiogenic potential of Ch-MSCs evidenced by a higher capability to form tubular vessel-like structures and an enhanced release of hepatocyte growth factor and vascular endothelial growth factor under hypoxic conditions. Our results suggest that assessing the prevalence of fetomaternal contamination within placental MSCs is necessary to increase robustness and limit side effects in their clinical use. Finally, our work presents evidence positioning fetoplacental cells and notably Ch-MSCs in the forefront of the quest for cell types that are superior for applications in regenerative medicine. © AlphaMed Press.

Alcayaga-Miranda F.,University of Los Andes, Chile | Gonzalez P.L.,University of Los Andes, Chile | Lopez-Verrilli A.,Cells for Cells | Varas-Godoy M.,University of Los Andes, Chile | And 3 more authors.
Oncotarget | Year: 2016

Mesenchymal stem cells (MSCs) secrete exosomes that are capable of modifying the tumor environment through different mechanisms including changes in the cancercell secretome. This activity depends on their cargo content that is largely defined by their cellular origin. Endometrial cells are fine regulators of the angiogenic process during the menstrual cycle that includes an angiostatic condition that is associated with the end of the cycle. Hence, we studied the angiogenic activity of menstrual stem cells (MenSCs)-secreted exosomes on prostate PC3 tumor cells. Our results showed that exosomes induce a reduction in VEGF secretion and NF-λB activity. Lower reactive oxygen species (ROS) production in exosomes-treated cells was detected by the DCF method, suggesting that the inhibition of the intracellular ROS impacts both NF-λB and VEGF pathways. We confirmed using tubule formation and plug transplantation assays that MenSCs-exosomes suppress the secretion of pro-angiogenic factors by the PC3 cells in a ROS-dependent manner. The inhibition of the tumor angiogenesis and, consequently, the tumor growth was also confirmed using a xenograft mouse model. Additionally, the anti-tumoral effect was associated with a reduction of tumor hemoglobin content, vascular density and inhibition of VEGF and HIF-1β expression. Importantly, we demonstrate that the exosomes anti-angiogenic effect is specific to the menstrual cell source, as bone marrow MSCs-derived exosomes showed an opposite effect on the VEGF and bFGF expression in tumor cells. Altogether, our results indicate that MenSCs-derived exosomes acts as blockers of the tumor-induced angiogenesis and therefore could be suitable for anti-cancer therapies.

The invention relates to highly proliferative stem cell obtained from menstrual fluid. The menstrual stern cells (MenSCs) may be cultured in vitro and exhibit mesenchymal stem cell (MSC)-like properties and some culture and expansion advantages. This population of MenSCs, compared to the broadly studied bone marrow derived stem cells (BM-MSCs) out-performs bone marrow derived mesenchymal stem cells in proliferation rate and support of hematopoietic stem cell (HSC) expansion in vitro. MenSCs demonstrate to maintain their stem cell properties over 2 years, being genetically stable, without expressing surface differentiation markers, and they also show the ability to differentiate into adipocytes, chondrocytes and osteoblast cells. MenSCs can be easily and periodically obtained, isolated and cultured.

Alcayaga-Miranda F.,University of Los Andes, Chile | Cuenca J.,University of Los Andes, Chile | Luz-Crawford P.,Cells for Cells | Luz-Crawford P.,French Institute of Health and Medical Research | And 4 more authors.
Stem Cell Research and Therapy | Year: 2015

Introduction: Stem cells isolated from menstrual fluid (MenSCs) exhibit mesenchymal stem cell (MSCs)-like properties including multi-lineage differentiation capacity. Besides, menstrual fluid has important advantages over other sources for the isolation of MSCs, including ease of access and repeated sampling in a noninvasive manner. Such attributes allow the rapid culture of MenSCs in numbers that are sufficient for therapeutical doses, at lower cell passages. Methods: In this study, we advance the characterization of MenSC populations in comparison to bone marrow derived mesenchymal stem cells (BM-MSCs) with regards to proliferation, lineage differentiation, migration potential, secretion profile and angiogenic properties in vitro and in a matrigel plug assay in mice. We additionally tested their ability to support hematopoietic stem cell (HSC) expansion in vitro. Results: The phenotypic analysis of MenSCs revealed a profile largely similar to the BM-MSCs with the exception of a higher expression of the adhesion molecule CD49a (alpha1-integrin). Furthermore, the fibroblast colony forming units (CFU-F) from MenSCs yielded a 2 to 4 fold higher frequency of progenitors and their in vitro migration capacity was superior to BM-MSCs. In addition, MenSCs evidenced a superior paracrine response to hypoxic conditions as evidenced by the secretion of vascular endothelial growth factor and basic fibroblast growth factor and also improved angiogenic effect of conditioned media on endothelial cells. Furthermore, MenSCs were able to induce angiogenesis in a matrigel plug assay in vivo. Thus, an 8-fold increase in hemoglobin content was observed in implanted plugs containing MenSCs compared to BM-MSCs. Finally, we demonstrated, for the first time, the capacity of MenSCs to support the ex-vivo expansion of HSCs, since higher expansion rates of the CD34∈+∈CD133+ population as well as higher numbers of early progenitor (CFU-GEMM) colonies were observed in comparison to the BM source. Conclusions: We present evidence showing superiority of MenSCs with respect to several functional aspects, in comparison with BM-MSCs. However, the impact of such properties in their use as adult-derived stem cells for regenerative3 medicine remains to be clarified. © 2015 Alcayaga-Miranda et al.; licensee BioMed Central.

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