Adipose-Induced Regeneration of Scalp (AIR-Scalp) to Treat Radiation Injury

Whole brain radiation therapy is a common treatment for cancer patients. After radiation, approximately 95% of the patients can experience acute and/or chronic side-effects: Radiation dermatitis, fibrosis, and chronic ulcers. The purpose of this study was to examine the effects of adipose-derived products (ADPs) in an animal model of radiation dermatitis. We hypothesized that ADPs would enhance wound healing and regenerate the skin; improving cellularity, vascularity, and decreasing scar tissue formation. Immunocompromised mice received a 0.5 cm skin incision on their scalp, which was closed with surgical glue. After 2 weeks, the mice received focal radiation using a 5 mm collimator: 0 Gy, 20 Gy single, and 40 Gy fractionated (8 Gy/day for 5 days) doses were used. After 2 weeks, mice were randomized into 4 groups and received a subcutaneous injection of 1) FAT-graft, 2) Stromal vascular fraction, 3) Adipose-derived mesenchymal stem cells, and 4) PBS. ADPs were isolated from lipoaspirate samples, obtained from non-cancer human patients. Two weeks after the ADPs treatments, mice were euthanized and skin samples were collected and processed for histology. Histological staining (H&E) was used to evaluate skin integrity after radiation. Results from the 20Gy group showed that the mice developed mild dermatitis 2 weeks after the radiation treatment that subsequently healed after ADPs treatment. No histological differences were observed between groups. While this study is ongoing (40Gy), it is hopeful that these results will offer an innovative way to treat radiation-induced damage in cancer patients

Editorial: Mesenchymal stromal cell therapy for regenerative medicine

Mesenchymal stromal/stem cell (MSC) therapies are increasingly explored as novel regenerative and immunomodulatory approaches to treat or prevent diseases (Pittenger et al., 2019; Hmadcha et al., 2020; Moll et al., 2020b; Ringdén et al., 2022). These cells exhibit potent paracrine properties that can modulate host immune responses, lower inflammation, and orchestrate endogenous tissue repair, at both the local and the systemic level through multiple pathways (Singer and Caplan, 2011; Doorn et al., 2012). MSCs possess tropism toward damaged and inflamed tissues, where they can engraft short-term and exert their therapeutic effects by both direct and indirect mechanisms (Doorn et al., 2012; Galipeau and Sensebe, 2018; Soria et al., 2019). MSC products can be prepared from multiple sources (Moll et al., 2019, 2022), rapidly expanded and biobanked for clinical application. All these advantages make this cell type a versatile tool in regenerative medicine. The goal of our Research Topic is to highlight the latest advances in applications of MSCs for the treatment of a variety of diseases and their modes of action (MoA). A better understanding of the mechanisms underlying the therapeutic effect of MSCs can provide crucial insight into innovative strategies to enhance their effectiveness in clinical application (Singer and Caplan, 2011; Doorn et al., 2012; Galipeau and Sensebe, 2018; Moll et al., 2019, 2020b, 2022; Pittenger et al., 2019; Ringdén et al., 2022). The subjects covered within this Research Topic include: (a) Therapeutic application of MSCs for major clinical indications, (b) Cellular and molecular mechanisms underlying therapeutic effects of MSCs, and (c) Strategies for enhancement of the therapeutic effects of MSCs and their products. Here, we summarize the 37 manuscripts that were submitted to this Research Topic (Figure 1)

Use of Mesenchymal Stem Cells in Pre-Clinical Models of Spinal Cord Injury

Spinal Cord Injury (SCI) is a devastating disease that causes disruption of sensorimotor function below the site of injury. Current management is based on surgical decompression of the neural tissue and pharmacotherapy; however, there is no gold standard treatment readily available for patients in the clinic. This indicates that novel therapeutic strategies for the treatment are still needed in the clinical setting. There are several alternatives that are currently under investigation for the treatment of this disease, with increasing focus in regenerative medicine treatments. Mesenchymal stem cells (MSCs) are one of the most promising candidates for stem cell therapy in SCI, as they are easily obtained, have high safety profiles, and help with neural regeneration in SCI mainly via release of trophic factors, neovascularization, and immunomodulation. In this work, authors provide an insight of the available MSC for neural regeneration, their therapeutic role, and the potential MSC-based therapies for SCI

Circulatory shear stress induces molecular changes and side population enrichment in primary tumor-derived lung cancer cells with higher metastatic potential

Abstract Cancer is a leading cause of death and disease worldwide. However, while the survival for patients with primary cancers is improving, the ability to prevent metastatic cancer has not. Once patients develop metastases, their prognosis is dismal. A critical step in metastasis is the transit of cancer cells in the circulatory system. In this hostile microenvironment, variations in pressure and flow can change cellular behavior. However, the effects that circulation has on cancer cells and the metastatic process remain unclear. To further understand this process, we engineered a closed-loop fluidic system to analyze molecular changes induced by variations in flow rate and pressure on primary tumor-derived lung adenocarcinoma cells. We found that cancer cells overexpress epithelial-to-mesenchymal transition markers TWIST1 and SNAI2, as well as stem-like marker CD44 (but not CD133, SOX2 and/or NANOG). Moreover, these cells display a fourfold increased percentage of side population cells and have an increased propensity for migration. In vivo, surviving circulatory cells lead to decreased survival in rodents. These results suggest that cancer cells that express a specific circulatory transition phenotype and are enriched in side population cells are able to survive prolonged circulatory stress and lead to increased metastatic disease and shorter survival

Preoperative Stereotactic Radiosurgery for Glioblastoma

SIMPLE SUMMARY: Stereotactic radiosurgery (SRS) is a multidisciplinary neurosurgical and radiation technique that allows for the delivery of a highly conformal dose of ionizing radiation with minimal radiation exposure to surrounding healthy tissues. SRS has been shown to be associated with excellent rates of local tumor control for multiple tumor types. Additionally, SRS has been shown to augment the effects of anti-tumor immunity. However, there is a paucity of evidence exploring the role of preoperative SRS in glioblastoma (GBM). To date, limited preclinical evidence has suggested that preoperative SRS has the potential to enhance anti-tumor immune responses and improve patient outcomes in glioma. In this review, we provide an overview of GBM and the role of preoperative radiosurgery in its management. ABSTRACT: Glioblastoma is a devastating primary brain tumor with a median overall survival of approximately 15 months despite the use of optimal modern therapy. While GBM has been studied for decades, modern therapies have allowed for a reduction in treatment-related toxicities, while the prognosis has largely been unchanged. Adjuvant stereotactic radiosurgery (SRS) was previously studied in GBM; however, the results were disappointing. SRS is a highly conformal radiation technique that permits the delivery of high doses of ionizing radiation in 1–5 sessions while largely sparing surrounding healthy tissues. Furthermore, studies have shown that the delivery of ablative doses of ionizing radiation within the central nervous system is associated with enhanced anti-tumor immunity. While SRS is commonly used in the definitive and adjuvant settings for other CNS malignancies, its role in the preoperative setting has become a topic of great interest due to the potential for reduced treatment volumes due to the treatment of an intact tumor, and a lower risk of nodular leptomeningeal disease and radiation necrosis. While early reports of SRS in the adjuvant setting for glioblastoma were disappointing, its role in the preoperative setting and its impact on the anti-tumor adaptive immune response is largely unknown. In this review, we provide an overview of GBM, discuss the potential role of preoperative SRS, and discuss the possible immunogenic effects of this therapy

Melatonin Treatment Triggers Metabolic and Intracellular pH Imbalance in Glioblastoma

Metabolic rewiring in glioblastoma (GBM) is linked to intra- and extracellular pH regulation. In this study, we sought to characterize the role of melatonin on intracellular pH modulation and metabolic consequences to identify the mechanisms of action underlying melatonin oncostatic effects on GBM tumor initiating cells. GBM tumor initiating cells were treated at different times with melatonin (1.5 and 3.0 mM). We analyzed melatonin’s functional effects on GBM proliferation, cell cycle, viability, stemness, and chemo-radiosensitivity. We then assessed the effects of melatonin on GBM metabolism by analyzing the mitochondrial and glycolytic parameters. We also measured the intracellular and extracellular pH. Finally, we tested the effects of melatonin on a mouse subcutaneous xenograft model. We found that melatonin downregulated LDHA and MCT4, decreasing lactate production and inducing a decrease in intracellular pH that was associated with an increase in ROS and ATP depletion. These changes blocked cell cycle progression and induced cellular death and we observed similar results in vivo. Melatonin’s cytotoxic effects on GBM were due, at least in part, to intracellular pH modulation, which has emerged as a newly identified mechanism, providing new insights into the oncostatic effect of melatonin on GBM