Mesenchymal stem cells (MSCs) are derived from mesoderm at the early stage of embryo development, and are a heterogeneous cell population. MSCs in the body contain stem cells and differentiating progeny from the early stages of embryonic development and thereafter. Almost all human tissues contain MSCs, which are abundant in various tissues and organs, such as bone marrow, fat, dental pulp, umbilical cord, and placenta. MSCs from different sources have different protein expression profiles, and their characteristics are slightly different, but they have functions such as self-renewal ability, multi-directional differentiation potential, and immune regulation.
MSCs differentiation has the potential to differentiate into a variety of cell types. By regulating the differential expression of genes under the stimulation of specific signals and local microenvironments, they can not only differentiate into cell types derived from mesoderm, including cardiomyocytes, vascular endothelial cells, and lipid, osteogenic and chondrogenic cells can also be transdifferentiated into cells derived from endoderm such as gastrointestinal epithelial cells, lung cells, intestinal epithelial cells, muscle cells, etc., and can also be transdifferentiated into epidermal cells such as epidermal cells and nerve cells. Multiple signaling pathways participate in the cell differentiation process of MSCs, of which the two major signaling pathways, Wnt and TGF-β families, play a key role in cell differentiation. Activation of Wnt signaling pathway receptors on the surface of bone marrow stem cells leads to downstream signal transduction to regulate cellular processes such as proliferation and differentiation of bone marrow stem cells. MSCs have the ability of multi-directional differentiation of mesenchymal stem cells tri-lineage and can be widely used in the fields of drug screening, tissue engineering and cell therapy.
Figure 1. The multi-directional differentiation potential of MSCs
The early stages of MSCs research focused on their self-renewal, differentiation potential and tissue regeneration capacity as adult stem cells, and proposed the mechanism of host cell replacement. The mechanism of MSCs cell replacement includes two aspects, cell trans-differentiation and cell fusion. Cell trans-differentiation refers to the migration of MSCs to tissue injury sites and differentiation across the germ layer under the mediation of chemokines. Tissue-specific cells and connected cells replace damaged cells to play a role in tissue regeneration and repair. Cell fusion refers to the fusion of MSCs with host cells, which leads to reprogramming of the host cell's nucleus, and the fused cells express MSCs-specific genes, thereby avoiding apoptosis in damaged host cells. The results of animal experiments and clinical trials show that, regardless of autologous or allogeneic MSCs transplantation, only a small number of cells can colonize and survive for longtime during tissue damage repair. But it is not the main mechanism that MSCs play a role as cell therapy. MSCs involved in tissue damage repair also involves a series of complex biological processes such as tissue endogenous stem / progenitor cell activation, immune regulation and inflammatory response.
The study found that different inflammatory microenvironments can polarize MSCs into two types similar to M1 / M2 macrophages, namely pro-inflammatory MSC1 and anti-inflammatory MSC2. When the tissue is damaged, the inflammatory factors secreted by the injury site make macrophages differentiate into M1 macrophages that promote inflammation. MSCs acquire the anti-inflammatory phenotype MSC2, which secretes a large amount of nitric oxide (NO) and indolamine 2,3-dioxygenase (IDO) to inhibit the function of lymphocytes and weaken the immune response to reduce tissue damage caused by excessive stress. In chronic inflammatory environment, macrophages differentiate into M2 macrophages that inhibit inflammation, at this time inflammatory factors such as IFN-γ and TNF-α are at low concentrations. It cannot activate the immunosuppressive function of MSCs, so that it can obtain the proinflammatory phenotype MSC1. MSC1 recruit lymphocytes to chemo to the inflammation area and activates them by secreting chemokines, and because of insufficient secretion of NO and IDO, these recruitments cannot be inhibited. The immune response of lymphocytes intensifies the intensity of the inflammatory response and causes tissue damage. This indicates that MSCs play a regulating and balancing role on the strength of mesenchymal stem cell immunomodulation. There is an important relationship between the activation of Toll-like receptors (TLRs) and the polarization of MSCs. TLRs is a special pattern recognition receptor. Its chemical structure is a type I transmembrane protein, which can recognize different disease-related molecular patterns (PAMPs) such as lipopolysaccharide (LPS), virus replication intermediate dsRNA, and heat shock protein. Signaling pathways, which stimulate immune cell responses, have an important effect on maintaining the homeostasis of the immune response during tissue injury sites. There are currently 11 members of the TLRs family that have been found to differ in expression in different cells. For example, TLR1 is expressed in monocytes, lymphocytes and NK cells. It is expressed in dendritic cells (DCs) and has important regulatory effects in both innate and adaptive immune responses. TLRs are also expressed on the surface of MSCs, among which TLR3 and TLR4 are highly expressed, which have an important effect on the polarization of MSCs. dsRNA can bind to TLR3 on the surface of MSCs, polarize MSCs to MSC2, and secrete anti-inflammatory factors NO, IDO, prostaglandin E2 (PGE2), transforming growth factor β (TGF-β), hepatocyte growth factor (HGF), etc. Inhibit the proliferation of T cells, promote the generation and activation of T regulatory cells (Tregs), and thus suppress the activation of immune functions. LPS can activate TLR4 on the surface of MSCs, polarize MSCs to MSC1 type, significantly reduce the production of anti-inflammatory factors, and secrete macrophage inflammatory protein 1α (MIP-1α), MIP-1β, CXC chemokine ligand 9 (CXCL9), regulating the activation of normal T cell expression and secretion factors (RANTES, CCL5) and other chemokines, recruit lymphocytes to chemoattract the site of inflammation and enhance the T cell-mediated immune response, and promote the occurrence of inflammatory response . Co-culture experiments of MSCs and tumor cells in vitro can also confirm that MSCs can have a two-way effect of suppressing and enhancing immunity after polarization: When co-cultured with MSC1 and tumor cells, it can inhibit tumor growth and reduce tumor cell migration ability and invasiveness; when MSC2 is co-cultured with tumor cells, it can promote tumor cell proliferation and increase value, which is conducive to growth.
The "nest" of stem cells is a special microenvironment on which stem cells depend. The "nest" can regulate the behavior of stem cells and keep stem cells growth, regeneration and differentiation of stem cells in balanced state. MSCs homing is defined as the process in which MSCs are captured in the vasculature of the target tissue and migrate through the vascular endothelial cells to the target tissue. The homing of MSCs is a continuous process, which manifests itself as the MSCs roll against the walls of the capillaries, then adhere to the surface of the endothelial cells and pass through the endothelial cells, and finally penetrate from the blood vessels to the target tissue. The mechanism of MSCs migrating across endothelial cells and homing to target tissues may involve the interaction of chemokines, growth factors, adhesion molecules and other receptors and their ligands expressed on the surface of MSCs. At present, more researches include stromal cell derived factor 1 (SDF-1), CXC chemokine receptor (CXCR), CC chemokine receptor (CCR), HGF and its receptor c-met (HGF / c- met), monocyte chemotactic protein (MCP), MIP and adhesion molecules, etc.
CXC chemokine: SDF-1 is also known as CXCL-12, and its receptor is CXCR4. It was first discovered in cytokines secreted by mouse bone marrow stromal cells and expressed on blood cells, hematopoietic stem cells, embryonic stem cells and other surfaces. The main function of the SDF-1 / CXCR4 axis is to regulate the chemotaxis and homing of precursor cells, which plays a key role in the recruitment and migration of MSCs. Compared with other chemokines, SDF-1 showed stronger chemotaxis ability to MSCs.
CC chemokine: A variety of CC chemokines, such as CCL2, CCL3, CCL4, CCL5, CCL7, etc. have chemotactic effects on cells. The expression of CCL2 and CCL3 is up-regulated in tissue injury and inflammation sites, while MSCs have the ability to be induced to express CC chemokine receptors. The study found that CCL3 is highly expressed in the myocardial infarction area of the experimental animal model of myocardial infarction. After treatment with MSCs, the heart with high CCL3 expression in the infarct area can recruit more MSCs, and myocardial function recovery is more significant than that of the control group. Overexpression of CCL3 receptor CCR1 can enhance the ability of MSCs to homing and implant into damaged myocardial tissue.
HGF / c- met: HGF is cytokine isolated from the serum of a partially hepatectomized rat model, which can promote DNA synthesis in liver cells. Its receptor is a tyrosine kinase called c-Met. After binding to c-met, HGF phosphorylates and initiates a specific signaling process. The HGF / c-met signaling pathway is widely involved in and regulates many physiological processes such as cell growth and migration, anti-apoptosis, promotion of proliferation and angiogenesis. Among them, HGF can promote the proliferation, migration and differentiation of MSCs, and mediate the targeted distribution of MSCs.
According to the new market research report "Cell Signaling Market by Type (Endocrine, Paracrine), Pathway (Akt, AMPK, Hedgehog, Notch), Product (Consumables, Instruments), Technology (Flow Cytometry, ELISA, Mass Spectrometry) & Application (Research, Cancer, Immunology) - Global Forecast", published by MarketsandMarkets™, report provides a detailed overview of the major drivers, restraints, challenges, opportunities, and strategies impacting the global market along with the estimates and forecasts of the revenue and market share analysis.The Cell Signaling Market is expected to reach USD 3.51 Billion, at a CAGR of 6.8%Download PDF Brochure:https://www.marketsandmarkets.com/pdfdownloadNew.asp?id=80206120 Growth in the market is driven by the rising incidence of chronic diseases, availability of funding for cell-based research, technological advancements in cell-based research instruments, and the growth of the life science and biopharmaceutical industries.This report segments the market on the basis of product, pathway, signaling type, technology, application, and region.Browse and in-depth TOC on “Cell Signaling Market”157 - Tables76 - Figures 212 - Pages Market Segmentation: By pathway, the market is segmented into AMP-activated protein kinase (AMPK), Akt, ErbB/HER, Hedgehog (Hh), NF-êB, Janus kinase and signal transducer and activator of transcription (JAK/STAT), Notch, and other signaling pathways.
The Akt pathway segment is estimated to account for the largest share of the market in 2017.Based on signaling type, the market is segmented into paracrine, endocrine, autocrine, juxtacrine, and other signaling types (intracrine and neuronal signaling).
The endocrine segment is estimated to account for the largest share of the Cell Signaling Market in 2017.On the basis of technology, the market is segmented into enzyme-linked immunosorbent assay (ELISA), immunohistochemistry (IHC), microscopy, flow cytometry, western blotting, mass spectrometry, and other technologies (immunofluorescence and immunoprecipitation).
The microscopy segment is estimated to account for the largest share in 2017.Based on application, the market is segmented into research applications (cancer research, immunology research, stem cells research, and other research applications) and medical applications.
The research applications segment is estimated to account for the largest share of the Cell Signaling Market in 2017.Request for Sample Report @ https://www.marketsandmarkets.com/pdfdownload.asp?id=80206120Geograghic Segmentation On the basis of region, the market is segmented into North America, Europe, Asia, and the Rest of the World (RoW).
North America is estimated to account for the largest share of the market in 2017.
