Stem cells are defined as cells able to both extensively self-renew and differentiate into progenitors. Research data show that more resistant stem cells than common cancer cells exist in cancer patients.To identify unrecognized differences between cancer stem cells and cancer cells might be able to develope effective classification,diagnose and treat ment for cancer.

Stem Cells,Cancer and Cancer Stem Cells

http://www.karplab.net/papers/Mesenchymal_Stem_Cell_Homing___The_Devil_Is_In_The_Details.pdf

Mesenchymal Stem Cell Homing: The Devil Is in the Details

https://journals.sagepub.com/doi/pdf/10.3727/096368915X689622

Clinical Trials with Mesenchymal Stem Cells: An Update:

In spite of the advances in the knowledge of adult stem cells (ASCs) during the past few years, their natural activities in vivo are still poorly understood. Mesenchymal stem cells (MSCs), one of the most promising types of ASCs for cell-based therapies, are defined mainly by functional assays using cultured cells. Defining MSCs in vitro adds complexity to their study because the artificial conditions may introduce experimental artifacts. Inserting these results in the context of the organism is difficult because the exact location and functions of MSCs in vivo remain elusive; the identification of the MSC niche is necessary to validate results obtained in vitro and to further the knowledge of the physiological functions of this ASC. Here we show an analysis of the evidence suggesting a perivascular location for MSCs, correlating these cells with pericytes, and present a model in which the perivascular zone is the MSC niche in vivo, where local cues coordinate the transition to progenitor and mature cell phenotypes. This model proposes that MSCs stabilize blood vessels and contribute to tissue and immune system homeostasis under physiological conditions and assume a more active role in the repair of focal tissue injury. The establishment of the perivascular compartment as the MSC niche provides a basis for the rational design of additional in vivo therapeutic approaches. This view connects the MSC to the immune and vascular systems, emphasizing its role as a physiological integrator and its importance in tissue repair/regeneration.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1634/stemcells.2007-1122

In search of the in vivo identity of mesenchymal stem cells

Mesenchymal stem cells (MSCs), the major stem cells for cell therapy, have been used in the clinic for approximately 10 years. From animal models to clinical trials, MSCs have afforded promise in the treatment of numerous diseases, mainly tissue injury and immune disorders. In this review, we summarize the recent opinions on methods, timing and cell sources for MSC administration in clinical applications, and provide an overview of mechanisms that are significant in MSC-mediated therapies. Although MSCs for cell therapy have been shown to be safe and effective, there are still challenges that need to be tackled before their wide application in the clinic.

/pdf/mesenchymal-stem-cells-a-new-trend-for-cell-therapy-5bzhdw859x.pdf

Mesenchymal stem cells: a new trend for cell therapy

Human mesenchymal stem cells (hMSCs) can home to tumor sites and inhibit the growth of tumor cells. Little is known about the underlying molecular mechanisms that link hMSCs to the targeted inhibition of tumor cells. In this study, we investigated the effects of hMSCs on two human hepatoma cell lines (H7402 and HepG2) using an animal transplantation model, a co-culture system and conditioned media from hMSCs. Animal transplantation studies showed that the latent time for tumor formation was prolonged and that the tumor size was smaller when SCID mice were injected with H7402 cells and an equal number of Z3 hMSCs. When co-cultured with Z3 cells, H7402 cell proliferation decreased, apoptosis increased, and the expression of Bcl-2, c-Myc, proliferating cell nuclear antigen (PCNA) and survivin was downregulated. After treatment with conditioned media derived from Z3 hMSC cultures, H4702 cells showed decreased colony-forming ability and decreased proliferation. Immunoblot analysis showed that beta-catenin, Bcl-2, c-Myc, PCNA and survivin expression was downregulated in H7402 and HepG2 cells. Taken together, our findings demonstrate that hMSCs inhibit the malignant phenotypes of the H7402 and HepG2 human liver cancer cell lines, which include proliferation, colony-forming ability and oncogene expression both in vitro and in vivo. Furthermore, our studies provide evidence that the Wnt signaling pathway may have a role in hMSC-mediated targeting and tumor cell inhibition.

/pdf/suppression-of-tumorigenesis-by-human-mesenchymal-stem-cells-1oswzt44zl.pdf

Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model.

Background and Objectives The use of mesenchymal stem cells (MSC) for cell therapy relies on the capacity of these cells to home and engraft long-term into the appropriate target tissue(s). Homing of MSC to bone marrow (BM) post-transplantation can occur, but does so with only poor efficiency. This study was designed to evaluate the role of the SDF-1/CXCR4 axis in the homing of Flk1+ MSC derived from human fetal BM.Design and Methods We investigated the expression of CXCR4 in Flk1+ MSC stimulated with a cytokine cocktail and explored their homing ability 24 hours after intravenous infusion into sublethally irradiated NOD/SCID mice. The peripheral blood was analyzed and human cells in recipients’ BM were quantified from 2 to 6 months after transplantation.Results We found that Flk1+ MSC harbored intracellular CXCR4 which can be rapidly induced to the cell surface within a few hours. Short-term (24 hours) stimulation with the cocktail of cytokines resulted in up-regulation of both cell surface and intracellular CXCR4, increasing in vitro migration capacity to SDF-1 and homing to the BM of irradiated NOD/SCID mice. Moreover, compared to non-treated cells, transplantation of cytokine-treated Flk1+ MSC resulted in faster hematologic recovery and higher levels of donor chimerism in BM. Neutralization of CXCR4 significantly reduced homing and engraftment of Flk1+ MSC in murine BM.Interpretation and Conclusions These results suggest that the SDF-1/CXCR4 axis plays an important role in the regulation of motility of Flk1+ MSC. Increasing CXCR4 expression might be a potential strategy to improve engraftment of MSC in BM and accelerate the recovery of hematopoiesis.

Regulation of CXCR4 expression in human mesenchymal stem cells by cytokine treatment: role in homing efficiency in NOD/SCID mice.

Background. Fibrosis is the common end stage of most liver diseases, for which, unfortunately, there is no effective treatment available currently. It has been shown that mesenchymal stem cells (MSCs) from bone marrow (BM) could engraft in the lung after bleomycin exposure and ameliorate its fibrotic effects. This study was designed to evaluate the effect of FIk1 + MSCs from murine BM (termed here Flk1 + mMSCs) on fibrosis formation induced by carbon tetrachloride (CCl 4 ). Methods. A CCl 4 -induced hepatic fibrosis model was used. Flk1 + mMSCs were systemically infused immediately or 1 week after mice were challenged with CCl 4 . Control mice received only saline infusion. Fibrosis index and donor-cell engraftment were assessed 2 or 5 weeks after CCl 4 challenge. Results. We found that Flk1 + mMSCs transplantation immediately, but not 1 week after exposure to CCl 4 , significantly reduced CCl 4 -induced liver damage and collagen deposition. In addition, levels of hepatic hydroxyproline and serum fibrosis markers in mice receiving immediate Flk1 + mMSCs transplantation after CCl 4 challenge were significantly lower compared with those of control mice. More importantly, histologic examination suggested that hepatic damage recovery was much better in these immediately Flk1 + mMSCs-treated mice. Immunofluorescence, polymerase chain reaction, and fluorescence in situ hybridization analysis revealed that donor cells engrafted into host liver, had epithelium-like morphology, and expressed albumin, although at low frequency. Conclusion. These results suggest that Flk1 + mMSCs might initiate endogenous hepatic tissue regeneration, engraft into host liver in response to CCl 4 injury, and ameliorate its fibrogenic effects.

Systemic infusion of FLK1(+) mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice.

Mesenchymal stem cells (MSCs) have profound immunomodulatory functions both in vitro and in vivo. However, their effects on the differentiation of dendritic cells (DCs) are unknown. In this study, we employed an in vitro model to investigate the effects of human MSCs on the development of DCs. CD34(+) cells isolated from cord blood were cultured under conventional DC(cDC) or plasmacytoid DC (pDC) differentiation conditions, in the presence or absence of MSCs or their conditioned medium. Here we show that both MSCs and their conditioned medium dramatically increased the numbers of cells generated under either condition. The percentage of cells with the cDC phenotype is significantly reduced in the presence of MSCs or their conditioned medium, whereas the percentage of pDC increased. The capacity of cDCs from MSCs or their conditioned medium-treated CD34(+) cells to stimulate allogeneic T cells was weakened. Furthermore, MSCs can skew the DC function from cDC to pDC, thus biasing the immune system toward Th2 and away from Th1 responses. Blocking the prostaglandin E(2) (PGE(2)) synthesis of MSCs can reverse most of these influences of MSCs on DCs differentiation and function. Therefore, MSCs can significantly influence DC development through PGE(2) production.

Mingxia Shi

Papers

Suppression of tumorigenesis by human mesenchymal stem cells in a hepatoma model.

Regulation of CXCR4 expression in human mesenchymal stem cells by cytokine treatment: role in homing efficiency in NOD/SCID mice.

Systemic infusion of FLK1(+) mesenchymal stem cells ameliorate carbon tetrachloride-induced liver fibrosis in mice.

Effects of human mesenchymal stem cells on the differentiation of dendritic cells from CD34+ cells.

Knockdown of hypoxia-inducible factor-1α in breast carcinoma MCF-7 cells results in reduced tumor growth and increased sensitivity to methotrexate