Animal Mesenchymal Stem Cells Research Articles

Mesenchymal Stem Cells Delivery in Individuals with Different Pathologies: Multimodal Tracking, Safety and Future Applications

Due to their ease of isolation and their properties, mesenchymal stem cells (MSCs) have been widely investigated. MSCs have been proved capable of migration towards areas of inflammation, including tumors. Therefore, they have been suggested as vectors to carry therapies, specifically to neoplasias. As most of the individuals joining clinical trials that use MSCs for cancer and other pathologies are carefully recruited and do not suffer from other diseases, here we decided to study the safety and application of iv-injected MSCs in animals simultaneously induced with different inflammatory pathologies (diabetes, wound healing and tumors). We studied this by in vitro and in vivo approaches using different gene reporters (GFP, hNIS, and f-Luc) and non-invasive techniques (PET, BLI, or fluorescence). Our results found that MSCs reached different organs depending on the previously induced pathology. Moreover, we evaluated the property of MSCs to target tumors as vectors to deliver adenoviruses, including the interaction between tumor microenvironment and MSCs on their arrival. Mechanisms such as transdifferentiation, MSC fusion with cells, or paracrine processes after MSCs homing were studied, increasing the knowledge and safety of this new therapy for cancer.

Stromal Vascular Fraction and Mesenchymal Stem Cells from Human Adipose Tissue: A Comparison of Immune Modulation and Angiogenic Potential.

In recent years, both stromal vascular fraction (SVF) from adipose tissue and mesenchymal stem cells (MSC) from adipose tissues were extensively used in both preclinical and clinical treatment for various diseases. Some studies reported differences in treatment efficacy between SVFs and MSCs in animals as well as in humans. Therefore, this study is aimed to evaluate the immune modulation and angiogenic potential of SVFs and MSCs from the same SVF samples to support an explanation when SVFs or MSCs should be used. The adipose tissue samples from ten female donors with consent forms were collected. SVFs from these samples were isolated according to the published protocols. The existence of mesenchymal cells that positive with CD44, CD73, CD90, and CD105 and endothelial progenitor cells that positive with CD31 and CD34 was determined using flow cytometry. Three samples of SVFs with similar percentages of mesenchymal cell portion and endothelial progenitor cell portion were used to isolate MSCs. Obtained MSCs were confirmed as MSCs using the ISCT minimal criteria. To compare the immune modulation of SVF and MSCs, the mixed lymphocyte assay was used. The lymphocyte proliferation, as well as IFN-gamma and TNF-alpha concentrations, were determined. To compare the angiogenic potential, the angiogenesis in quail embryo assay was used. The angiogenesis efficacy was measured based on the vessel areas formed in the embryos after 7days. The results showed that all SVF samples contained the portions of mesenchymal cells and endothelial progenitor cells. MSCs from SVFs meet all minimal criteria of MSCs that suggested by ISCT. MSCs from SVFs efficiently suppressed the immune cell proliferation compared to the SVFs, especially at ratios of 1:4 (1 MSCs: 4 immune cells). MSCs also inhibited the IFN-gamma and TNF-alpha production more efficiently than SVFs (p<0.05). However, in quail embryo models, SVFs triggered the angiogenesis and neovessel formation better than MSCs with more significant vessel areas after 7days (p<0.05). This study suggested that SVFs and MSCs have different potentials for immune modulation and angiogenesis. SVFs help the angiogenesis better than MSCs, while MSCs displayed the more significant immune modulation. These results can guide the usage of SVFs or MSCs in disease treatment.

Mesenchymal stem cells immortalization's and state-of-art: a systematic review and meta-analysis

Abstract Background The immortalization of mesenchymal stem cells (MSCs) allows them to avoid senescence and be cultured through limitless cell passages. Thus, several experimental strategies, such as retrovirus-mediated gene transfer or viral oncogenesis, have been applied for the immortalization of MSCs. The aim was to identifier the most commonly used methodologies and their particularities for the immortalization of human and animal MSCs. Methods The search was conducted in June 2019 and developed in SCOPUS, PUBMED, and SCIENCE DIRECT. Statistical analysis was performed, obtaining the values of total n, mean and standard deviation, confidence interval (CI), and percentage (frequency) for all the predictors. Results The most used immortalization methodology was viral transfection, being the most common immortalized cell type was the bone marrow-derived MSC, and the most used gene for immortalizing both human and animal MSCs was hTERT (39.3%) and SV40T (54.5%). Among the articles analyzed in this review, only 39.3% and 36.4% of human and animal MSCs immortalization protocols, respectively, underwent the tumorigenicity test. Conclusions The virus-mediated gene transfection was observed as the most used and established technique. The insertion of the hTERT gene is still the most used gene for cell immortalization, suggesting that the maintenance of telomerase is efficient for maintaining cell proliferation and bypassing cell senescence. The review concluded that the tumorigenicity tests should become mandatory in order to safely use the immortalized MSCs for translation.

Substantial Overview on Mesenchymal Stem Cell Biological and Physical Properties as an Opportunity in Translational Medicine.

Mesenchymal stem cells (MSC) have piqued worldwide interest for their extensive potential to treat a large array of clinical indications, their unique and controversial immunogenic and immune modulatory properties allowing ample discussions and debates for their possible applications. Emerging data demonstrating that the interaction of biomaterials and physical cues with MSC can guide their differentiation into specific cell lineages also provide new interesting insights for further MSC manipulation in different clinical applications. Moreover, recent discoveries of some regulatory molecules and signaling pathways in MSC niche that may regulate cell fate to distinct lineage herald breakthroughs in regenerative medicine. Although the advancement and success in the MSC field had led to an enormous increase in the amount of ongoing clinical trials, we still lack defined clinical therapeutic protocols. This review will explore the exciting opportunities offered by human and animal MSC, describing relevant biological properties of these cells in the light of the novel emerging evidence mentioned above while addressing the limitations and challenges MSC are still facing.

Dynamic Tracking Human Mesenchymal Stem Cells Tropism following Smoke Inhalation Injury in NOD/SCID Mice.

Multiple preclinical evidences have supported the potential value of mesenchymal stem cells (MSCs) for treatment of acute lung injury (ALI). However, few studies focus on the dynamic tropism of MSCs in animals with acute lung injury. In this study, we track systemically transplanted human bone marrow-derived mesenchymal stem cells (hBMSCs) in NOD/SCID mice with smoke inhalation injury (SII) through bioluminescence imaging (BLI). The results showed that hBMSCs systemically delivered into healthy NOD/SCID mouse initially reside in the lungs and then partially translocate to the abdomen after 24 h. Compared with the uninjured control group treated with hBMSCs, higher numbers of hBMSCs were found in the lungs of the SII NOD/SCID mice. In both the uninjured and SII mice, the BLI signals in the lungs steadily decreased over time and disappeared by 5 days after treatment. hBMSCs significantly attenuated lung injury, elevated the levels of KGF, decreased the levels of TNF-α in BALF, and inhibited inflammatory cell infiltration in the mice with SII. In conclusion, our findings demonstrated that more systemically infused hBMSCs localized to the lungs in mice with SII. hBMSC xenografts repaired smoke inhalation-induced lung injury in mice. This repair was maybe due to the effect of anti-inflammatory and secreting KGF of hMSCs but not associated with the differentiation of the hBMSCs into alveolar epithelial cells.

Could donor multipotent mesenchymal stromal cells prevent or delay the onset of diabetic retinopathy?

Diabetes mellitus is a complex metabolic disease that has become a global epidemic with more than 285 million cases worldwide. Major medical advances over the past decades have substantially improved its management, extending patients' survival. The latter is accompanied by an increased risk of developing chronic macro- and microvascular complications. Amongst them, diabetic retinopathy (DR) is the most common and frightening. Furthermore, during the past two decades, it has become the leading cause of visual loss. Irrespective of the type of diabetes, DR follows a well-known clinical and temporal course characterized by pericytes and neuronal cell loss, formation of acellular-occluded capillaries, occasional microaneurysms, increased leucostasis and thickening of the vascular basement membrane. These alterations progressively affect the integrity of retinal microvessels, leading to the breakdown of the blood-retinal barrier, widespread haemorrhage and neovascularization. Finally, tractional retinal detachment occurs leading to blindness. Nowadays, there is growing evidence that local inflammation and oxidative stress play pivotal roles in the pathogenesis of DR. Both processes have been associated with pericytes and neuronal degeneration observed early during DR progression. They may also be linked to sustained retinal vasculature damage that results in abnormal neovascularization. Currently, DR therapeutic options depend on highly invasive surgical procedures performed only at advanced stages of the disease, and which have proved to be ineffective to restore visual acuity. Therefore, the availability of less invasive and more effective strategies aimed to prevent or delay the onset of DR is highly desirable. Multipotent mesenchymal stromal cells, also referred to as mesenchymal stem cells (MSCs), are promising healing agents as they contribute to tissue regeneration by pleiotropic mechanisms, with no evidence of significant adverse events. Here, we revise the pathophysiology of DR to identify therapeutic targets for donor MSCs. Also, we discuss whether an MSC-based therapy could prevent or delay the onset of DR.

Safety of Intravenous Infusion of Human Adipose Tissue-Derived Mesenchymal Stem Cells in Animals and Humans

Adipose tissue-derived mesenchymal stem cells (AdMSCs) represent an attractive and ethical cell source for stem cell therapy. With the recent demonstration of MSC homing properties, intravenous applications of MSCs to cell-damaged diseases have increased. In the present study, the toxicity and tumorigenicity of human AdMSCs (hAdMSCs) were investigated for clinical application. Culture-expanded hAdMSCs showed the typical appearance, immunophenotype, and differentiation capacity of MSCs, and were genetically stable at least 12 passages in culture. Cells suspended in physiological saline maintained their MSC properties in a cold storage condition for at least 3 days. To test the toxicity of hAdMSCs, different doses of hAdMSCs were injected intravenously into immunodeficient mice, and the mice were observed for 13 weeks. Even at the highest cell dose (2.5×10(8) cells/kg body weight), the SCID mice were viable and had no side effects. A tumorigenicity test was performed in Balb/c-nu nude mice for 26 weeks. Even at the highest cell dose (2×10(8) MSCs/kg), no evidence of tumor development was found. In a human clinical trial, 8 male patients who had suffered a spinal cord injury >12 months previous were intravenously administered autologous hAdMSCs (4×10(8) cells) one time. None of the patients developed any serious adverse events related to hAdMSC transplantation during the 3-month follow-up. In conclusion, the systemic transplantation of hAdMSCs appears to be safe and does not induce tumor development.

Phenotype and chondrogenic differentiation of mesenchymal cells from adipose tissue of different species

Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into several mesoderm lineages. They have been isolated from different tissues, such as bone marrow, adult peripheral blood, umbilical cord blood, and adipose tissue. The aim of this study was to analyze the differences in proliferation and phenotype of adipose tissue-derived MSCs from three different species, and to evaluate their capacity to differentiate into chondrocytes in vitro. A comparative study of cultured human, rabbit, and sheep mesenchymal cells from adipose tissue was carried out, and the main morphological parameters, proliferative activity, and expression of surface markers were characterized. Proliferation and flow cytometry data showed species-related differences between animal and human MSCs. Histological staining suggested that rabbit and sheep mesenchymal cells were able to differentiate into chondrocytic lineages. Human mesenchymal cells, though they could also differentiate, accomplished it with more difficulty than animal MSCs. These results could help to explain the differences in the chondrogenic capacity of sheep and rabbit MSCs when they are used as animal models compared to human mesenchymal cells in a clinical assay.