The role of oxygen tension in cell fate and regenerative medicine: implications of hypoxia/hyperoxia and free radicals.

Oxygen pressure plays an integral role in regulating various aspects of cellular biology. Cell metabolism, proliferation, morphology, senescence, metastasis, and angiogenesis are some instances that are affected by different tensions of oxygen. Hyperoxia or high oxygen concentration, enforces the production of reactive oxygen species (ROS) that disturbs physiological homeostasis, and consequently, in the absence of antioxidants, cells and tissues are directed to an undesired fate. On the other side, hypoxia or low oxygen concentration, impacts cell metabolism and fate strongly through inducing changes in the expression level of specific genes. Thus, understanding the precise mechanism and the extent of the implication of oxygen tension and ROS in biological events is crucial to maintaining the desired cell and tissue function for application in regenerative medicine strategies. Herein, a comprehensive literature review has been performed to find out the impacts of oxygen tensions on the various behaviors of cells or tissues.

Mesenchymal stromal cells and CAR-T cells in regenerative medicine: The homing procedure and their effective parameters.

Mesenchymal stromal cells (MSCs) and chimeric antigen receptor (CAR)-T cells are two core elements in cell therapy procedures. MSCs have significant immunomodulatory effects that alleviate inflammation in the tissue regeneration process, while administration of specific chemokines and adhesive molecules would primarily facilitate CAR-T cell trafficking into solid tumors. Multiple parameters affect cell homing, including the recipient's age, the number of cell passages, proper cell culture, and the delivery method. In addition, several chemokines are involved in the tumor microenvironment, affecting the homing procedure. This review discusses parameters that improve the efficiency of cell homing and significant cell therapy challenges. Emerging comprehensive mechanistic strategies such as non-systemic and systemic homing that revealed a significant role in cell therapy remodeling were also reviewed. Finally, the primary implications for the development of combination therapies that incorporate both MSCs and CAR-T cells for cancer treatment were discussed.

Wharton's jelly mesenchymal stem cells transplantation for critical limb ischemia in patients with type 2 diabetes mellitus: a preliminary report of phase I clinical trial.

Peripheral artery disease (PAD) affects more than 230 million people worldwide, with approximately 11% of patients presenting with advanced-stage PAD or critical limb ischemia (CLI). To avoid or delay amputation, particularly in no-option CLI patients with infeasible or ineffective revascularization, new treatment strategies such as regenerative therapies should be developed. Mesenchymal stem cells (MSCs) are the most popular cell source in regenerative therapies. They possess significant characteristics such as angiogenic, anti-inflammatory, and immunomodulatory activities, which encourage their application in different diseases. This phase I clinical trial reports the safety, feasibility, and probable efficacy of the intramuscular administration of allogeneic Wharton's jelly-derived MSCs (WJ-MSCs) in type 2 diabetes patients with CLI. Out of six screened patients with CLI, five patients were administered WJ-MSCs into the gastrocnemius, soleus, and the proximal part of the tibialis anterior muscles of the ischemic lower limb. The safety of WJ-MSCs injection was considered a primary outcome. Secondary endpoints included wound healing, the presence of pulse at the disease site, the absence of amputation, and improvement in visual analogue scale (VAS), pain-free walking time, and foot and ankle disability index (FADI). No patient experienced adverse events and foot or even toe amputation during the 6-month follow-up. Six months after the intervention, there were a significantly lower VAS score and significantly higher pain-free walking time and FADI score than the baseline, but no statistically significant difference was seen between other time points. In conclusion, allogeneic WJ-MSC transplantation in patients with CLI seems to be safe and effective.

Disulfiram ameliorates bleomycin induced pulmonary inflammation and fibrosis in rats.

Bleomycin (BL) is a widely used anticancer drug that can cause pulmonary fibrosis due to increased fibroblast proliferation and increased secretion of extracellular matrix. RASSF1A is a tumor suppressor gene that is down-regulated by DNA methylation during fibrosis. Disulfiram (DSF), a noncytosine DNA methyltransferase inhibitor, can revert epigenetic biomarkers and re-express silenced genes. We investigated anti-inflammatory and anti-fibrotic effects of DSF on regulation of epigenetic molecules and histopathology in a rat model of BL induced pulmonary fibrosis. We used six groups of rats: sesame oil (SO) control (Co) group, BL group, BL + SO group and three BL + DSF groups administered 1 mg/kg DSF (BL + DSF), 10 mg/kg DSF (BL + DSF10) or 100 mg/kg DSF (BL + DSF100), respectively. BL was administered intratracheally to induce pulmonary fibrosis. DSF and SO were injected intraperitoneally (i.p.) 2 days before BL administration; these injections were continued for 3 weeks. At the end of the study, lung tissues were removed for molecular and histopathologic studies. Administration of 10 or 100 mg/kg DSF after BL induced pulmonary inflammation and fibrosis, and up-regulated RASSF1A and down-regulated TNF-α and IL-1 ß compared to the BL and BL + SO groups. A RASSF1A unmethylated band was observed using the methylation-specific PCR technique in rats that had been administered 10 and 100 mg/kg DSF, which indicated partial DNA demethylation. Histopathologic evaluation revealed that fibrosis and all inflammatory scores were decreased significantly in the BL + DSF10 and BL + DSF100 groups compared to the BL group. Our findings indicate that DSF modified DNA methylation by up-regulating RASSF1A, which reduced inflammation and fibrosis in BL induced pulmonary inflammation and fibrosis.

Extracellular vesicles as a new horizon in the diagnosis and treatment of inflammatory eye diseases: A narrative review of the literature.

Extracellular vesicles include exosomes, microvesicles, and apoptotic bodies. Their cargos contain a diverse variety of lipids, proteins, and nucleic acids that are involved in both normal physiology and pathology of the ocular system. Thus, studying extracellular vesicles may lead to a more comprehensive understanding of the pathogenesis, diagnosis, and even potential treatments for various diseases. The roles of extracellular vesicles in inflammatory eye disorders have been widely investigated in recent years. The term "inflammatory eye diseases" refers to a variety of eye conditions such as inflammation-related diseases, degenerative conditions with remarkable inflammatory components, neuropathy, and tumors. This study presents an overview of extracellular vesicles' and exosomes' pathogenic, diagnostic, and therapeutic values in inflammatory eye diseases, as well as existing and potential challenges.

Composition, Biogenesis, and Role of Exosomes in Tumor Development.

The role of exosomes and their mechanism of action at the tumor site have received increasing attention. These microvesicles are produced by a wide range of cells including mesenchymal stem cells (MSCs) and immune cells. In particular, tumor cells release remarkable amounts of exosomes which spread to distant organs through the blood and enhance the possibility of tumor metastasis. In spite of results on tumor promoting properties, there are reports demonstrating the tumor inhibiting effects of exosomes depending on the type of the tumor and cell source. This review aims to have a comprehensive appraisal on the biogenesis, composition, and isolation of exosomes and then highlights the current knowledge of their role in cancer progression or inhibition by special focusing on MSC's exosomes (MSC-EXOs).

Optimization of Nanoclay/Polyacrylonitrile Scaffold Using Response Surface Method for Bone Differentiation of Human Mesenchymal Stem Cells.

Response surface methodology (RSM) based on the D-optimal algorithm was employed here for the electrospinning of nanoclay/polyacrylonitrile (PAN) composite scaffold by the aim of obtaining the lower fiber diameter and better mechanical properties for bone regeneration. The input parameters included the electrospinning voltage, flow rate and the ratio of nanoclay/PAN and the obtained values for the optimum point were 17 kV for the applied voltage, 0.41 ml/hr for flow rate, and 19.06% for the nanoclay/PAN ratio. The composite scaffold was fabricated in accordance with these optimum values and then studied by scanning electron microscopy and tensile apparatus. The fiber diameter and Young's modulus of the prepared scaffold were respectively 145 ± 12 nm and 267 ± 8.7 MPa that the values were between predicted by RSM. Moreover, the biocompatibility and osteogenic differentiation of the composite scaffold were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and alkaline phosphatase assays. The bare scaffold and tissue culture polystyrene were used as control groups. The results approved stronger bioactivity and bone regeneration with the composite scaffold as a presence of clay nanoparticles.

Tracking of GFP-labeled unrestricted somatic stem cells transplanted in the sepsis mouse model.

Cell-based therapy provides a promising approach for the treatment of sepsis and related disorders. Fate determination of transplanted cells is the most essential issue for cell therapist. Optical imaging is the reliable, time and cost-effective system for cell tracking. The present study was aimed to apply an optical imaging system for monitoring of GFP-labeled unrestricted somatic stem cells in the sepsis animal model. In vivo imaging showed the most accumulation of intravenously injected cells into the lungs and liver of septic mice. Thereafter, the imaging data were more approved by flow cytometry and immunohistochemistry staining. Cellular localization in septic lungs and liver that observed by optical imaging technique may offer beneficial evidence for designing of sepsis clinical trials.