In recent decades, the biomedical applications of mesenchymal stem cells (MSCs) have attracted increasing attention. MSCs are easily extracted from the bone marrow, fat, and synovium, and differentiate into various cell lineages according to the requirements of specific biomedical applications. As MSCs do not express significant histocompatibility complexes and immune stimulating molecules, they are not detected by immune surveillance and do not lead to graft rejection after transplantation. These properties make them competent biomedical candidates, especially in tissue engineering. We present a brief overview of MSC extraction methods and subsequent potential for differentiation, and a comprehensive overview of their preclinical and clinical applications in regenerative medicine, and discuss future challenges.

https://www.mdpi.com/2073-4409/8/8/886/pdf

Mesenchymal Stem Cells for Regenerative Medicine.

Broad targeting of resistance to apoptosis in cancer.

Chronic non-healing wounds show delayed and incomplete healing processes and in turn expose patients to a high risk of infection. Treatment currently focuses on dressings that prevent microbial infiltration and keep a balanced moisture and gas exchange environment. Antibacterial delivery from dressings has existed for some time, with responsive systems now aiming to trigger release only if infection occurs. Simultaneously, approaches that stimulate cell proliferation in the wound and encourage healing have been developed. Interestingly, few dressings appear capable of simultaneously impairing or treating infection and encouraging cell proliferation/wound healing. Electrospinning is a simple, cost-effective, and reproducible process that can utilize both synthetic and natural polymers to address these specific wound challenges. Electrospun meshes provide high-surface area, micro-porosity, and the ability to load drugs or other biomolecules into the fibers. Electrospun materials have been used as scaffolds for tissue engineering for a number of years, but there is surprisingly little literature on the interactions of fibers with bacteria and co-cultures of cells and bacteria. This Review examines the literature and data available on electrospun wound dressings and the research that is required to develop smart multifunctional wound dressings capable of treating infection and healing chronic wounds.

Electrospun Nanofibers as Dressings for Chronic Wound Care: Advances, Challenges, and Future Prospects

Cancer is the second leading cause of death globally. Although, there are many different approaches to cancer treatment, they are often painful due to adverse side effects and are sometimes ineffective due to increasing resistance to classical anti-cancer drugs or radiation therapy. Targeting delayed/inhibited apoptosis is a major approach in cancer treatment and a highly active area of research. Plant derived natural compounds are of major interest due to their high bioavailability, safety, minimal side effects and, most importantly, cost effectiveness. Flavonoids have gained importance as anti-cancer agents and have shown great potential as cytotoxic anti-cancer agents promoting apoptosis in cancer cells. In this review, a summary of flavonoids and their effectiveness in cancer treatment targeting apoptosis has been discussed.

https://www.mdpi.com/2072-6694/11/1/28/pdf

Flavonoids in Cancer and Apoptosis.

Electrospun hydroxyapatite-containing chitosan nanofibers crosslinked with genipin for bone tissue engineering

The polyphenol epigallocatechin-3-gallate (EGCG) in combination with doxorubicin (Dox) exhibits a synergistic activity in blocking the growth and colony-forming ability of human prostate cell lines in vitro. EGCG has been found to disrupt the mitochondrial membrane potential, induce vesiculation of mitochondria, and induce elevated poly (ADP-ribose) polymerase (PARP) cleavage and apoptosis. EGCG in combination with low levels of Dox had a synergistic effect in blocking tumor cell growth. In vivo tumor modeling studies with a highly metastatic tumor line, PC-3ML cells, revealed that EGCG (228 mg/kg or 200 μmol/L) appeared to sensitize tumors to Dox. EGCG combined with low levels of Dox (0.14 mg/kg or 2 μmol/L) blocked tumor growth by PC-3ML cells injected intraperitoneally (ie, in CB17 severe combined immunodeficiencies) and significantly increased mouse survival rates. Similarly, relatively low levels of EGCG (57 mg/kg or 50 μmol/L) plus Dox (0.07 mg/kg or 1 μmol/L) eradicated established tumors (ie, in nonobese diabetic–severe combined immunodeficiencies) that were derived from CD44hi tumor-initiating cells isolated from PCa-20a cells. Flow cytometry results showed that EGCG appeared to enhance retention of Dox by tumor cells to synergistically inhibit tumor growth and eradicate tumors. These data suggest that localized delivery of high dosages of EGCG combined with low levels of Dox may have significant clinical application in the treatment of metastatic prostate and/or eradication of primary tumors derived from tumor-initiating cells.

Combination Therapy with Epigallocatechin-3-Gallate and Doxorubicin in Human Prostate Tumor Modeling Studies: Inhibition of Metastatic Tumor Growth in Severe Combined Immunodeficiency Mice

Understanding the initial mechanisms by which epithelial cells transform to an invasive phenotype is critical to the development of diagnostics that can identify the metastatic potential of cancers as well as therapeutic agents that can prevent metastases. Changes in cellular response to the transforming growth factor-beta (TGF-β) cytokine are known to promote epithelial cell invasion and metastasis in part through induction of epithelial–mesenchymal transitions (EMTs). In this report, we demonstrate that non-metastatic human prostate cancer cell lines of increasing Gleason score can be induced to undergo EMT when treated with TGF-β in combination with epidermal growth factor. Mechanistic studies revealed that in cells stably transfected with activated Ras, TGF-β alone induced EMT and that a Ras-Raf-MEK1, but not MEK2, signaling cascade is necessary and sufficient for Erk2 nuclear localization that works in concert with TGF-β to promote EMT. Furthermore, we show for the first time that expression of the transcription factor c-myc, which is phosphorlyated by Erk2, is required for EMT. Characteristically, EMT involved adoption of a spindle-shaped morphology, loss of E-cadherin and increased expression of Vimentin, Fibronectin and Fibroblast Specific Protein-1 (S100A4). Prostate cells undergoing EMT became invasive and expressed several genes associated with metastasis, including MT-MMP1, MMP-2/9, the MMP-9 homodimer, Slug and Twist2. In sum, we demonstrate a novel mechanism by which non-invasive primary prostate tumor cells transition to an invasive phenotype characteristic of malignant tumor cells in response to TGF-β signaling.

c-Myc expression and MEK1-induced Erk2 nuclear localization are required for TGF- beta induced epithelial-mesenchymal transition and invasion in prostate cancer

Injectable carboxymethylcellulose hydrogels for soft tissue filler applications

As a potential alternative to currently available skin substitutes and wound dressings, we explored the use of bioactive scaffolds made of plant-derived proteins. We hypothesized that 'green' materials, derived from renewable and biodegradable natural sources, may confer bioactive properties to enhance wound healing and tissue regeneration. We optimized and characterized fibrous scaffolds electrospun from soy protein isolate (SPI) with addition of 0.05% poly(ethylene oxide) (PEO) dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol, and from corn zein dissolved in glacial acetic acid. Fibrous mats electrospun from either of these plant proteins remained intact without further cross-linking, possessing a skin-like pliability. Soy-derived scaffolds supported the adhesion and proliferation of cultured primary human dermal fibroblasts. Using targeted PCR arrays and qPCR validation, we found similar gene expression profiles of fibroblasts cultured for 2 and 24 h on SPI substrates and on collagen type I at both time points. On both substrates there was a pronounced time-dependent upregulation of several genes related to ECM deposition remodelling, including MMP-10, MMP-1, collagen VII, integrin-α2 and laminin-β3, indicating that both plant- and animal-derived materials induce similar responses from the cells after initial adhesion, degrading substrate proteins and depositing extracellular matrix in a 'normal' remodelling process. These results suggest that 'green' proteins, such as soy and zein, are promising as a platform for organotypic skin equivalent culture, as well as implantable scaffolds for skin regeneration. Future studies will determine specific mechanisms of their interaction with skin cells and their efficacy in wound-healing applications.

Devika M. Varma

Papers

Combination Therapy with Epigallocatechin-3-Gallate and Doxorubicin in Human Prostate Tumor Modeling Studies: Inhibition of Metastatic Tumor Growth in Severe Combined Immunodeficiency Mice

c-Myc expression and MEK1-induced Erk2 nuclear localization are required for TGF- beta induced epithelial-mesenchymal transition and invasion in prostate cancer

Injectable carboxymethylcellulose hydrogels for soft tissue filler applications

Alimentary ‘green’ proteins as electrospun scaffolds for skin regenerative engineering

Development of crosslinked methylcellulose hydrogels for soft tissue augmentation using an ammonium persulfate-ascorbic acid redox system.