Biological Characteristics Of Mesenchymal Stem Cells Research Articles

Current problems and persprectives of the treatment of cartilage injuries using mesenchimal stem cells

Annotation. Since standard methods of treatment of cartilage trauma and inflammatory diseases lack effectiveness, at present one of the most promising strategies is mesenchymal stem cell transplantation. Despite the successes in this field, many issues, such as the selection of the tissue-source of mesenchymal stem cells (MSCs) and their optimization or modification in culture in order to achieve the maximum therapeutic effect, remains an actual task for both global and domestic scientists. The purpose of the study is to prepare a review of literature sources for the period 2004-2022 (in the vast majority on publications of the last five years) and to systematize new data on the biological characteristics of MSCs from various tissue sources, which are used in strategies for the treatment of cartilage lesions tissues, to analyze existing problems and further prospects, as well as potential ways of optimizing MSC cultivation methods to increase their regenerative potential. A study of 49 sources that met the inclusion criteria was carried out. A significant variety of strategies for the use of MSCs in animal models and in clinical practice was revealed. The main mechanisms ensuring the therapeutic effect of MSCs have been determined and can be used as criteria for optimizing cellular material. However, it was found that the question of the effectiveness of the use of differentiated MSCs, the selection of the tissue-source of MSCs, and the specifics of the use of MSCs from neonatal sources remains open. Thus, the analysis of literary sources revealed further promising ways to improve the therapeutic efficiency of MSC grafting in a wide range of cartilaginous lesions. There is a need to research the effects of MSCs from neonatal tissues, and especially the umbilical cord. This will become possible due to experimental research that will be carried out in the future.

The role of microenvironment in stem cell-based regeneration of intervertebral disc

Regenerative medicine for intervertebral disc (IVD) disease, by utilizing chondrocytes, IVD cells, and stem cells, has progressed to clinical trials in the treatment of back pain, and has been studied in various animal models of disc degeneration in the past decade. Stem cells exist in their natural microenvironment, which provides vital dynamic physical and chemical signals for their survival, proliferation and function. Long-term survival, function and fate of mesenchymal stem cells (MSCs) depend on the microenvironment in which they are transplanted. However, the transplanted MSCs and the endogenous disc cells were influenced by the complicated microenvironment in the degenerating disc with the changes of biochemical and biophysical components. It is important to understand how the MSCs and endogenous disc cells survive and thrive in the harsh microenvironment of the degenerative disc. Furthermore, materials containing stem cells and their natural microenvironment have good clinical effects. However, the implantation of tissue engineering IVD (TE-IVD) cannot provide a complete and dynamic microenvironment for MSCs. IVD graft substitutes may need further improvement to provide the best engineered MSC microenvironment. Additionally, the IVD progenitor cells inside the stem cell niches have been regarded as popular graft cells for IVD regeneration. However, it is still unclear whether actual IVD progenitor cells exist in degenerative spinal conditions. Therefore, the purpose of this review is fourfold: to discuss the presence of endogenous stem cells; to review and summarize the effects of the microenvironment in biological characteristics of MSC, especially those from IVD; to explore the feasibility and prospects of IVD graft substitutes and to elaborate state of the art in the use of MSC transplantation for IVD degeneration in vivo as well as their clinical application.

Administration of mesenchymal stem cells in diabetic kidney disease: mechanisms, signaling pathways, and preclinical evidence.

Diabetic kidney disease (DKD) is a serious microvascular complication of diabetes. Currently, the prevalence and mortality of DKD are increasing annually. However, with no effective drugs to prevent its occurrence and development, the primary therapeutic option is to control blood sugar and blood pressure. Therefore, new and effective drugs/methods are imperative to prevent the development of DKD in patients with diabetes. Mesenchymal stem cells (MSCs) with multi-differentiation potential and paracrine function have received extensive attention as a new treatment option for DKD. However, their role and mechanism in the treatment of DKD remain unclear, and clinical applications are still being explored. Given this, we here provide an unbiased review of recent advances in MSCs for the treatment of DKD in the last decade from the perspectives of the pathogenesis of DKD, biological characteristics of MSCs, and different molecular and signaling pathways. Furthermore, we summarize information on combination therapy strategies using MSCs. Finally, we discuss the challenges and prospects for clinical application.

Gamma-glutamyltransferase of Helicobacter pylori alters the proliferation, migration, and pluripotency of mesenchymal stem cells by affecting metabolism and methylation status.

Virulence factor gamma-glutamyltransferase (GGT) of H. pylori consumes glutamine (Gln) in the stomach to decrease the tricarboxylic acid metabolite alpha-ketoglutarate (α-kg) and alter the downstream regulation of α-kg as well as cellular biological characteristics. Our previous research indicated that under H. pylori infection, mesenchymal stem cells (MSCs) migrated to the stomach and participated in gastric cancer (GC) development either by differentiating into epithelial cells or promoting angiogenesis. However, how MSCs themselves participate in H. pylori-indicated GC remains unclear. Therefore, a GGT knockout H. pylori strain (Hp-KS-1) was constructed, and downstream histone H3K9 and H3K27 methylation and the PI3K/AKT signaling pathway of α-kg were detected using Western blotting. The biological characteristics of MSCs were also examined. An additive α-kg supplement was also added to H. pylori-treated MSCs to investigate alterations in these aspects. Compared to the control and Hp-KS-1 groups, H. pylori-treated MSCs reduced Gln and α-kg, increased H3K9me3 and H3K27me3, activated the PI3K-AKT signaling pathway, and promoted the proliferation, migration, self-renewal, and pluripotency of MSCs. The addition of α-kg rescued the H. pylori-induced alterations. Injection of MSCs to nude mice resulted in the largest tumors in the H. pylori group and significantly reduced tumor sizes in the Hp-KS-1 and α-kg groups. In summary, GGT of H. pylori affected MSCs by interfering with the metabolite α-kg to increase trimethylation of histone H3K9 and H3K27, activating the PI3K/AKT signaling pathway, and promoting proliferation, migration, self-renewal, and pluripotency in tumorigenesis, elucidating the mechanisms of MSCs in GC development.

Comparison of biological characteristics of placenta mesenchymal stem cells derived from fetus

Mesenchymal stem cells (MSCs) have broad application potentials in regenerative medicine and translational medicine. Obtaining large quantities of primary-cultured MSCs and select the most suitable cell origin for targeted diseases are critical to research. To select the most suitable seed cells of MSCs from different origins for clinical treatment and research, biological characteristics of MSCs from human umbilical cord and placenta were compared. These include cell morphology, surface marker expression, differentiation and karyotype. Transcriptome sequencing of four MSCs from fetus were performed and the results were analyzed from the perspective of proliferation and cytokine secretion. The results revealed that MSCs from umbilical cord (UC), amniotic membrane (AM), chorionic membrane (CM), chorionic villi (CV) and deciduae (DC) met the minimum standards of the International Society of Cell Therapy (ISCT) in 2006 and had the general characteristics of stem cells. Karyotype analysis showed that MSCs derived from UC, AM, CM and CV were all from fetus except that the DC-MSCs were from mother. Transcriptome sequencing analysis showed that hMSCs from umbilical cord and placenta had similar gene expression patterns, while different expression patterns were observed in specific genes involved in cell cycle, cell division, cell death, cell growth and development. These genes play important roles in transcriptional regulation, DNA repair, DNA replication and chromosome stability, which were momentous components of cellular or subcellular fraction movement, cell communication, cell tissue protrusions, cytokine secretion and hormone metabolism. Transcriptome sequencing analysis explained the differences in biological characteristics among MSCs from different sources, while verification experiments based on the transcriptome sequencing results showed that the proliferation and cytokine secretion capabilities of MSCs from different sources were significantly different. In all, UC-MSCs and CV-MSCs with stronger proliferation and higher levels of paracrine factors secretion may show their respective advantages in treating diseases.

Changes of Migration, Immunoregulation and Osteogenic Differentiation of Mesenchymal Stem Cells in Different Stages of Inflammation.

Bone infection has always been the focus of orthopedic research. Mesenchymal stem cells (MSCs) are the natural progenitors of osteoblasts, and the process of osteogenesis is triggered in response to different signals from the extracellular matrix. MSCs exert important functions including secretion and immune regulation and also play a key role in bone regeneration. The biological behavior of MSCs in acute and chronic inflammation, especially the transformation between acute inflammation and chronic inflammation, has aroused great interest among researchers. This paper reviews the recent literature and summarizes the behavior and biological characteristics of MSCs in acute and chronic inflammation to stimulate further research on MSCs and treatment of bone diseases.

HGF-Modified Dental Pulp Stem Cells Mitigate the Inflammatory and Fibrotic Responses in Paraquat-Induced Acute Respiratory Distress Syndrome.

Paraquat (PQ) poisoning can cause acute lung injury and progress to pulmonary fibrosis and eventually death without effective therapy. Mesenchymal stem cells (MSCs) and hepatocyte growth factor (HGF) have been shown to partially reverse this damage. MSCs can be derived from bone marrow (BM-MSCs), adipose tissue (AD-MSCs), umbilical cord (UC-MSCs), dental pulp (DPSCs), and other sources. The biological characteristics of MSCs are specific to the tissue source. To develop an effective treatment for PQ poisoning, we compared the anti-inflammatory and antifibrotic effects of UC-MSCs and DPSCs and chose and modified a suitable source with HGF to investigate their therapeutic effects in vitro and in vivo. In this study, MSCs' supernatant was beneficial to the viability and proliferation of human lung epithelial cell BEAS-2B. Inflammatory and fibrosis-related cytokines were analyzed by real-time PCR. The results showed that MSCs' supernatant could suppress the expression of proinflammatory and profibrotic cytokines and increase the expression of anti-inflammatory and antifibrotic cytokines in BEAS-2B cells and human pulmonary fibroblast MRC-5. Extracellular vesicles (EVs) derived from MSCs performed more effectively than MSCs' supernatant. The effect of DPSCs was stronger than that of UC-MSCs and was further strengthened by HGF modification. PQ-poisoned mice were established, and UC-MSCs, DPSCs, and DPSCs-HGF were administered. Histopathological assessments revealed that DPSCs-HGF mitigated lung inflammation and collagen accumulation more effectively than the other treatments. DPSCs-HGF reduced lung permeability and increased the survival rate of PQ mice from 20% to 50%. Taken together, these results indicated that DPSCs can suppress inflammation and fibrosis in human lung cells better than UC-MSCs. The anti-inflammatory and antifibrotic effects were significantly enhanced by HGF modification. DPSCs-HGF ameliorated pulmonitis and pulmonary fibrosis in PQ mice, effectively improving the survival rate, which might be mediated by paracrine mechanisms. The results suggested that DPSCs-HGF transplantation was a potential therapeutic approach for PQ poisoning.

Advances of Researchs on Molecular Mechanisms of Mesenchymal Stem Cells and Their Exosomes in Angiogenesis--Review

Mesenchymal stem cells (MSC) have the potential of multi-directional differentiation, and can recruit endothelial cells, promote their proliferation, migration and angiogenesis, improve blood perfusion and oxygen suppliment, and repair damaged tissue. Exosome secreted by MSC contain mother cell-specific proteins, lipids and nucleic acids, and acts as signaling molecule, playing an important role in cell communication, thereby altering target cell function. In this review, the biological characteristics of MSC and its exosome, the mechanism of promoting vascular regeneration in patients with ischemic diseases, and the mechanism of hypoxia-inducible factor-1α（HIF-1α） in the vascular ischemia of ischemic diseases are all summarized briefly.

Bone Tissue Regeneration - Application of Mesenchymal Stem Cells and Cellular and Molecular Mechanisms.

The regeneration of damaged bone tissues to a pre-disease state has been a major goal for both clinicians and researchers worldwide. However, critical-sized bone defects which are unable to heal completely are a major clinical concern because effective, evidencebased regenerative therapy is still missing. Bone tissue engineering, aiming at providing novel and effective materials to promote bone regeneration, has been considered as a promising alternative to the traditional use of autografts, allografts and xenografts based on the fact that engineered bone tissue has limitless supply and has no disease transmission. Mesenchymal stem cells (MSCs) can be derived from various adult tissues such as adipose tissues, dental follicles of wisdom teeth, bone marrow, dental pulp, gingiva, etc., which do not raise any ethical concerns. Furthermore, the application of MSCs in bone tissue engineering has moved to the preclinical stage, and an ex vivo cell manufacturing procedure for obtaining high quality, bioactive MSCs from human bone marrow has been approved by the US Food and Drug Administration (FDA). In this review, we summarized the cell sources and biological characteristics of MSCs, discussed the in vivo functions of MSCs during bone regeneration, and briefly introduced the strategies for the application of MSCs in bone tissue engineering. Further research efforts are still needed to facilitate the application of MSCs in enhancing bone regeneration.

Mesenchymal stem cell-based therapy in kidney transplantation

Kidney transplantation is the best treatment for end-stage renal disease, but its implementation is limited by organ shortage and immune rejection. Side effects of current immunosuppressive drugs, such as nephrotoxicity, opportunistic infection, and tumorigenic potential, influence long-term graft outcomes. In recent years, continued research and subsequent discoveries concerning the properties and potential utilization of mesenchymal stem cells (MSCs) have aroused considerable interest and expectations. Biological characteristics of MSCs, including multi-lineage differentiation, homing potential, paracrine effect and immunomodulation, have opened new horizons for applications in kidney transplantation. However, many studies have shown that the biological activity of MSCs depends on internal inflammatory conditions, and the safety and efficacy of the clinical application of MSCs remain controversial. This review summarizes the findings of a large number of studies and aims to provide an objective viewpoint based on a comprehensive analysis of the presently established benefits and obstacles of implementing MSC-based therapy in kidney transplantation, and to promote its clinical translation.

Lymphocyte inhibition is compromised in mesenchymal stem cells from psoriatic skin.

Psoriasis is a chronic inflammatory skin disorder associated with a host of immune abnormalities. Mesenchymal stem cells (MSCs) have immunosuppressive properties and, in earlier studies, we found that the bone marrow MSCs of patients with psoriasis exhibit abnormal cytokine secretion. Since MSCs can be isolated from skin, we hypothesized that the biological characteristics of MSCs in psoriatic skin lesions might reflect the pathogenesis of psoriasis. To investigate the effects of MSCs from psoriatic skin lesions on T-cell proliferation. MSCs obtained from psoriatic skin lesions and healthy human skin were examined by flow cytometry and cell differentiation assays. MSCs were co-cultured with normal peripheral blood T cells to assess changes in T-cell proliferation. Concentrations of interleukin (IL)-6, IL-11, hepatocyte growth factor (HGF), and transforming growth factor (TGF)-β1 in the MSC culture supernatants were measured by enzyme-linked immunosorbent assays. Surface markers and differentiation capacity were similar in MSCs from both sources. MSCs in psoriatic skin lesions were weaker inhibitors of T-cell proliferation (p<0.05) and exhibited increased secretion of IL-11 and reduced secretion of IL-6 and HGF (p<0.05). Secretion of TGF-β1 was unchanged (p > 0.05). This study demonstrated abnormalities in MSCs derived from psoriatic skin lesions. We suggest that the attenuated inhibitory effect on T-cell proliferation might be one of the pathogenic mechanisms of psoriasis.

Pleiotropic effects of cancer cells’ secreted factors on human stromal (mesenchymal) stem cells

IntroductionStudying cancer tumors’ microenvironment may reveal a novel role in driving cancer progression and metastasis. The biological interaction between stromal (mesenchymal) stem cells (MSCs) and cancer cells remains incompletely understood. Herein, we investigated the effects of tumor cells’ secreted factors as represented by a panel of human cancer cell lines (breast (MCF7 and MDA-MB-231); prostate (PC-3); lung (NCI-H522); colon (HT-29) and head & neck (FaDu)) on the biological characteristics of MSCs.MethodsMorphological changes were assessed using fluorescence microscopy. Changes in gene expression were assessed using Agilent microarray and qRT-PCR. GeneSpring 12.1 and DAVID tools were used for bioinformatic and signaling pathway analyses. Cell migration was assessed using a transwell migration system. SB-431542, PF-573228 and PD98059 were used to inhibit transforming growth factor β (TGFβ), focal adhesion kinase (FAK), and mitogen activated protein kinase kinase (MAPKK) pathways, respectively. Interleukin-1β (IL1β) was measured using ELISA.ResultsMSCs exposed to secreted factors present in conditioned media (CM) from FaDu, MDA-MB-231, PC-3 and NCI-H522, but not from MCF7 and HT-29, developed an elongated, spindle-shaped morphology with bipolar processes. In association with phenotypic changes, genome-wide gene expression and bioinformatics analysis revealed an enhanced pro-inflammatory response of those MSCs. Pharmacological inhibitions of FAK and MAPKK severely impaired the pro-inflammatory response of MSCs to tumor CM (approximately 80% to 99%, and 55% to 88% inhibition, respectively), while inhibition of the TGFβ pathway was found to promote the pro-inflammatory response (approximately 3-fold increase). In addition, bioinformatics and pathway analysis of gene expression data from tumor cell lines combined with experimental validation revealed tumor-derived IL1β as one mediator of the pro-inflammatory phenotype observed in MSCs exposed to tumor CM.MSCs exhibited significant tropism toward secreted factors from the aforementioned tumor cell lines, while both normal and MSCs exposed to tumor CM were capable of attracting human peripheral blood mononuclear cells (PBMCs).ConclusionsOur data revealed tumor-derived IL1β as one mediator of the pro-inflammatory response in MSCs exposed to tumor CM, which was found to be positively regulated by FAK and MAPK signaling and negatively regulated by TGFβ signaling. Thus, our data support a model where MSCs could promote cancer progression through becoming pro-inflammatory cells within the cancer stroma.

Abnormalities in cytokine secretion from mesenchymal stem cells in psoriatic skin lesions

Psoriasis is a chronic inflammatory and proliferative skin disease associated with immune abnormalities. In our preliminary studies, it was found that bone marrow mesenchymal stem cells (BMSCs) were abnormal in patients with psoriasis. Mesenchymal stem cells (MSCs) are not only present in the bone marrow, but can also be separated from the skin.We reasoned that an investigation into the biological characteristics of MSCs in psoriatic skin lesions could more realistically reflect the actual conditions for the pathogenesis of psoriasis. To reveal whether MSCs in psoriatic skin lesions are abnormal. We obtained MSCs from psoriatic skin lesions and healthy human skin and identified these cells using flow cytometry and a cell differentiation assay; cytokine concentrations in the culture supernatants were measured with the ELISA assay. We compared cytokine concentrations in culture supernatants of MSCs derived from psoriatic skin lesions as well as those from healthy human skin. Compared with healthy control skintissue, in psoriatic skin lesions, MSC secretion of EGF, SCF, and IL-11 increased; secretion of bFGF, IL-3, IL-6, IL-8, and HGF decreased (p<0.05); and secretion of VEGF, M-CSF, G-CSF, GM-CSF, LIF, IL-1, IL-7, IL-10, and TNF-α showed no significant difference (p>0.05). Surface markers and the differentiation capacity of cells from the two sources were similar. This study demonstrated that MSCs derived from psoriatic skin lesions had abnormalities, which may be one of the pathogenic mechanisms of psoriasis.

Mesenchymal stem cell and its application in the treatment of liver disease

Mesenchymal stem cells (MSCs) have been the hot spot of rehabilitation and tissue engineered medicine.Due to their origination from the adult tissues,the multilineage differentiation potential and immune escape characteristics,MSCs become the ideal seed cells for cell transplant treatment.This article summarizes the biological characteristics of MSCs and its application in the treatment of liver disease. Key words: Mesenchymal stem cell; liver disease; Treatment

353. Biological Comparison of Mesenchymal Stem Cells Derived from Bone Marrow and Adipose Tissue

The potential of adult mesenchymal stem cells (MSCs) to differentiate to diverse cell types in vitro and in vivo offers outstanding opportunities to use these cells as therapeutic agents. The biological characteristics of MSCs isolated from two distinct tissues, bone marrow and adipose tissue were evaluated in vitro and in vivo. MSCs derived from human and non-human primate (rhesus monkey) tissue sources were compared. The data indicate that MSCs isolated from rhesus bone marrow (rBMSCs) and human adipose tissue (hASCs) had more similar biologic properties than MSCs ofrhesus adipose tissue (rASCs) and human bone marrow MSCs (hBMSCs). Analyses of in vitro growth kinetics revealed shorter doubling time for rBMSCs and hASCs. rBMSCs and hASCs underwent significantly more population doublings than the other MSCs. MSCs from all sources showed a marked decrease in telomerase activity over extended culture; however they maintained their mean telomere length. All of the MSCs expressed embryonic stem cell markers, Oct-4, Rex-1 and Sox-2 for at least 10 passages. Early populations of MSCs types showed similar multilineage differentiation capability. However, only the rBMSCs and hASCs retain greater differentiation efficiency at higher passages. Overall in vitro characterization of MSCs from these two species and tissue sources revealed a high level of common biologic properties. The bone marrow and adipose tissue derived MSCs were then compared for the plasticity in vivo. In a time course study, the two types of MSCs were transplanted into the lateral ventricles of NIHIII immune deficient mice. The migration and engraftment of MSCs have been evaluated on 2, 4, and 6 weeks post engraftment. Our results indicated that while both cell types engrafted in multiple regions throughout the brain, the adipose tissue derived MSCs persisted in the brain for longer periods of time. The adipose tissue derived MSCs were detected up to six weeks post-transplantation. Since there is no ethical limitation on using adult stem cells, the results of this study suggest that adipose tissue and bone marrow will prove to be important sources of pluripotent stem cells.