Understanding global communications among cells requires accurate representation of cell-cell signaling links and effective systems-level analyses of those links. We construct a database of interactions among ligands, receptors and their cofactors that accurately represent known heteromeric molecular complexes. We then develop CellChat, a tool that is able to quantitatively infer and analyze intercellular communication networks from single-cell RNA-sequencing (scRNA-seq) data. CellChat predicts major signaling inputs and outputs for cells and how those cells and signals coordinate for functions using network analysis and pattern recognition approaches. Through manifold learning and quantitative contrasts, CellChat classifies signaling pathways and delineates conserved and context-specific pathways across different datasets. Applying CellChat to mouse and human skin datasets shows its ability to extract complex signaling patterns. Our versatile and easy-to-use toolkit CellChat and a web-based Explorer ( http://www.cellchat.org/ ) will help discover novel intercellular communications and build cell-cell communication atlases in diverse tissues.

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Inference and analysis of cell-cell communication using CellChat.

Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.

/pdf/targeting-cancer-stem-cell-pathways-for-cancer-therapy-26ugvhsqd5.pdf

Targeting cancer stem cell pathways for cancer therapy

http://chemotaxis.semmelweis.hu/CHTXhpg/Durotaxis/DT2/ProvenzanoPP_BiophysJ_2008.pdf

Contact Guidance Mediated Three-Dimensional Cell Migration is Regulated by Rho/ROCK-Dependent Matrix Reorganization

Mesenchymal stem cells (MSCs) are a heterogeneous population of stem/progenitor cells with pluripotent capacity to differentiate into mesodermal and non-mesodermal cell lineages, including osteocytes, adipocytes, chondrocytes, myocytes, cardiomyocytes, fibroblasts, myofibroblasts, epithelial cells, and neurons. MSCs reside primarily in the bone marrow, but also exist in other sites such as adipose tissue, peripheral blood, cord blood, liver, and fetal tissues. When stimulated by specific signals, these cells can be released from their niche in the bone marrow into circulation and recruited to the target tissues where they undergo in situ differentiation and contribute to tissue regeneration and homeostasis. Several characteristics of MSCs, such as the potential to differentiate into multiple lineages and the ability to be expanded ex vivo while retaining their original lineage differentiation commitment, make these cells very interesting targets for potential therapeutic use in regenerative medicine and tissue engineering. The feasibility for transplantation of primary or engineered MSCs as cell-based therapy has been demonstrated. In this review, we summarize the current knowledge on the signals that control trafficking and differentiation of MSCs.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jcb.22091

Trafficking and differentiation of mesenchymal stem cells

The molecular mechanisms underlying angioimmunoblastic T cell lymphoma (AITL), a common type of mature T cell lymphoma of poor prognosis, are largely unknown. Here we report a frequent somatic mutation in RHOA (encoding p.Gly17Val) using exome and transcriptome sequencing of samples from individuals with AITL. Further examination of the RHOA mutation encoding p.Gly17Val in 239 lymphoma samples showed that the mutation was specific to T cell lymphoma and was absent from B cell lymphoma. We demonstrate that the RHOA mutation encoding p.Gly17Val, which was found in 53.3% (24 of 45) of the AITL cases examined, is oncogenic in nature using multiple molecular assays. Molecular modeling and docking simulations provided a structural basis for the loss of GTPase activity in the RHOA Gly17Val mutant. Our experimental data and modeling results suggest that the RHOA mutation encoding p.Gly17Val is a driver mutation in AITL. On the basis of these data and through integrated pathway analysis, we build a comprehensive signaling network for AITL oncogenesis.

A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma

Mesenchymal stem cells (MSC) can differentiate into several cell types and are desirable candidates for cell therapy and tissue engineering. However, due to poor cell survival, proliferation and differentiation in the patient, the therapy outcomes have not been satisfactory. Although several studies have been done to understand the conditions that promote proliferation, differentiation and migration of MSC in vitro and in vivo, still there is no clear understanding on the effect of non-cellular bio molecules. Of the many factors that influence the cell behavior, the immediate cell microenvironment plays a major role. In this context, we studied the effect of extracellular matrix (ECM) proteins in controlling cell survival, proliferation, migration and directed MSC differentiation. We found that collagen promoted cell proliferation, cell survival under stress and promoted high cell adhesion to the cell culture surface. Increased osteogenic differentiation accompanied by high active RHOA (Ras homology gene family member A) levels was exhibited by MSC cultured on collagen. In conclusion, our study shows that collagen will be a suitable matrix for large scale production of MSC with high survival rate and to obtain high osteogenic differentiation for therapy.

/pdf/collagen-promotes-higher-adhesion-survival-and-proliferation-516zg2qxh9.pdf

Collagen Promotes Higher Adhesion, Survival and Proliferation of Mesenchymal Stem Cells

Although mesenchymal stromal cells (MSCs) are being increasingly used as cell therapeutics in clinical trials, the mechanisms that regulate their chemotactic migration behavior are incompletely understood. We aimed to better define the ability of the GTPase regulator of cytoskeletal activation, Rho, to modulate migration induction in MSCs in a transwell chemotaxis assay. We found that culture-expanded MSCs migrate poorly toward exogenous phospholipids lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) in transwell assays. Moreover, plasma-induced chemotactic migration of MSCs was even inhibited after pretreatment with LPA. LPA treatment activated intracellular Rho and increased actin stress fibers in resident MSCs. Very similar cytoskeletal changes were observed after microinjection of a cDNA encoding constitutively active RhoA (RhoAV14) in MSCs. In contrast, microinjection of cDNA encoding Rho inhibitor C3 transferase led to resolution of actin stress fibers, appearance of a looser actin meshwork, and increased numbers of cytoplasmic extensions in the MSCs. Surprisingly, in LPA-pretreated MSCs migrating toward plasma, simultaneous addition of Rho inhibitor C2I-C3 reversed LPA-induced migration suppression and led to improved migration. Moreover, addition of Rho inhibitor C2I-C3 resulted in an approximately 3- to 10-fold enhancement of chemotactic migration toward LPA, S1P, as well as platelet-derived growth factor or hepatocyte growth factor. Thus, inhibition of Rho induces rearrangement of actin cytoskeleton in MSCs and renders them susceptible to induction of migration by physiological stimuli. Disclosure of potential conflicts of interest is found at the end of this article.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1634/stemcells.2007-0167

Rho inhibition induces migration of mesenchymal stromal cells.

THY1 (CD90) is a 25–37-kDa heavily N-glycosylated, glycophosphatidylinositol (GPI) anchored cell surface protein. It is usually expressed on thymocytes, mesenchymal stem cells, hematopoietic stem cells, natural killer cells, neurons, endothelial cells, renal glomerular mesangial cells, follicular dendritic cells, fibroblasts, and myofibroblasts. It has been found to regulate cell adhesion, migration, apoptosis, axon growth, cell-cell and cell-matrix interactions, T-cell activation, and fibrosis. Several reports have shown that CD90 has an important role in cancer in regulating cancer cell proliferation, metastasis, and angiogenesis. There are also evidences that CD90 is an important prognostic marker in many cancers. Consequently, therapies that target CD90 have great promise in treating many cancers. However, several studies also indicate a contradictory role for CD90, where it acts as a tumor suppressor. In this review, we summarize the expression, function of CD90 in different cancers and its possible use as a biomarker or a therapeutic target in cancer. The challenges and future prospects for the use of CD90 for clinical applications are also discussed in this review.

Multiple roles of CD90 in cancer

Mesenchymal Stem Cells (MSC) are important candidates for therapeutic applications due to their ex vivo proliferation and differentiation capacity. MSC differentiation is controlled by both intrinsic and extrinsic factors and actin cytoskeleton plays a major role in the event. In the current study, we tried to understand the initial molecular mechanisms and pathways that regulate the differentiation of MSC into osteocytes or adipocytes. We observed that actin modification was important during differentiation and differentially regulated during adipogenesis and osteogenesis. Initial disruption of actin polymerization reduced further differentiation of MSC into osteocytes and osteogenic differentiation was accompanied by increase in ERK1/2 and p38 MAPK phosphorylation. However, only p38 MAPK phosphorylation was down regulated upon inhibition of actin polymerization which as accompanied by decreased CD49E expression. Taken together, our results show that actin modification is a pre-requisite for MSC differentiation into osteocytes and adipocytes and osteogenic differentiation is regulated through p38 MAPK phosphorylation. Thus by modifying their cytoskeleton the differentiation potential of MSC could be controlled which might have important implications for tissue repair and regeneration.

/pdf/inhibition-of-actin-polymerization-decreases-osteogeneic-3cszhxpcf2.pdf

Inhibition of actin polymerization decreases osteogeneic differentiation of mesenchymal stem cells through p38 MAPK pathway

Mesenchymal Stem Cells (MSCs) have been studied extensively for the treatment of several retinal diseases. The therapeutic potential of MSCs lies in its ability to differentiate into multiple lineages and secretome enriched with immunomodulatory, anti-angiogenic and neurotrophic factors. Several studies have reported the role of MSCs in repair and regeneration of the damaged retina where the secreted factors from MSCs prevent retinal degeneration, improve retinal morphology and function. MSCs also donate mitochondria to rescue the function of retinal cells and exosomes secreted by MSCs were found to have anti-apoptotic and anti-inflammatory effects. Based on several promising results obtained from the preclinical studies, several clinical trials were initiated to explore the potential advantages of MSCs for the treatment of retinal diseases. This review summarizes the various properties of MSCs that help to repair and restore the damaged retinal cells and its potential for the treatment of retinal degenerative diseases.

/pdf/a-review-on-mesenchymal-stem-cells-for-treatment-of-retinal-4gssitbmtx.pdf

Bithiah Grace Jaganathan

Papers

Collagen Promotes Higher Adhesion, Survival and Proliferation of Mesenchymal Stem Cells

Rho inhibition induces migration of mesenchymal stromal cells.

Multiple roles of CD90 in cancer

Inhibition of actin polymerization decreases osteogeneic differentiation of mesenchymal stem cells through p38 MAPK pathway

A Review on Mesenchymal Stem Cells for Treatment of Retinal Diseases.