Mensenchymal stem cells can delay radiation-induced crypt death: impact on intestinal CD44(+) fragments.

Intestinal stem cells are primitive cells found within the intestinal epithelium that play a central role in maintaining epithelial homeostasis through self-renewal and commitment into functional epithelial cells. Several markers are available to identify intestinal stem cells, such as Lgr5, CD24 and EphB2, which can be used to sort intestinal stem cells from mammalian gut. Here, we identify and isolate intestinal stem cells from C57BL/6 mice by using a cell surface antigen, CD44. In vitro, some CD44(+) crypt cells are capable of forming "villus-crypt"-like structures (organoids). A subset strongly positive for CD44 expresses high levels of intestinal stem-cell-related genes, including Lgr5, Bmi1, Hopx, Lrig1, Ascl2, Smoc2 and Rnf43. Cells from this subset are more capable of developing into organoids in vitro, compared with the subset weakly positive for CD44. However, the organoids are sensitive to ionizing irradiation. We investigate the specific roles of mesenchymal stem cells in protecting organoids against radiation-induced crypt death. When co-cultured with mesenchymal stem cells, the crypt domains of irradiated organoids possess more proliferative cells and fewer apoptotic cells than those not co-cultured with mesenchymal stem cells. Cd44v6 continues to be expressed in the crypt domains of irradiated organoids co-cultured with mesenchymal stem cells. Our results indicate specific roles of mesenchymal stem cells in delaying radiation-induced crypt death in vitro.

Metastatic thymic-enteric adenocarcinoma responding to chemoradiation plus anti-angiogenic therapy: A case report.

BACKGROUND: Thymic-enteric adenocarcinoma with positive expression of CDX2 and CK20 is rare in adults, with only 16 reported cases. However, standard treatment options for this type of thymic adenocarcinoma has not yet been established. Therefore, we report a case of stage IV thymic-enteric adenocarcinoma treated with radiotherapy, chemotherapy, and anti-angiogenesis therapy. CASE SUMMARY: We report a case of thymic-enteric adenocarcinoma occurring in a 44-year-old woman. The tumor was considered unresectable owing to its invasiveness. The patient was treated with six cycles of oxaliplatin (130 mg/m2, day 1) and capecitabine (1000 mg/m2 BID, days 1-14). During the first three cycles of chemotherapy, concurrent radiotherapy (60 Gy/30 fractions) and anti-angiogenic therapy using apatinib were recommended. The primary tumor achieved partial remission based on the Response Evaluation Criteria in Solid Tumors. During follow-up, there was no evidence of disease relapse, except a high serum CA19-9 level. The patient is alive and regularly followed. Based on the previous literature and the present case, we believe that early diagnosis of thymic-enteric adenocarcinoma is important. CONCLUSION: XELOX (capecitabine plus oxaliplatin) combined with radiotherapy is an optional therapy for inoperable thymic-enteric adenocarcinoma.

Gut commensal bacteria, Paneth cells and their relations to radiation enteropathy.

In steady state, the intestinal epithelium forms an important part of the gut barrier to defend against luminal bacterial attack. However, the intestinal epithelium is compromised by ionizing irradiation due to its inherent self-renewing capacity. In this process, small intestinal bacterial overgrowth is a critical event that reciprocally alters the immune milieu. In other words, intestinal bacterial dysbiosis induces inflammation in response to intestinal injuries, thus influencing the repair process of irradiated lesions. In fact, it is accepted that commensal bacteria can generally enhance the host radiation sensitivity. To address the determination of radiation sensitivity, we hypothesize that Paneth cells press a critical "button" because these cells are central to intestinal health and disease by using their peptides, which are responsible for controlling stem cell development in the small intestine and luminal bacterial diversity. Herein, the most important question is whether Paneth cells alter their secretion profiles in the situation of ionizing irradiation. On this basis, the tolerance of Paneth cells to ionizing radiation and related mechanisms by which radiation affects Paneth cell survival and death will be discussed in this review. We hope that the relevant results will be helpful in developing new approaches against radiation enteropathy.

Decoding epigenetic codes: new frontiers in exploring recovery from spinal cord injury.

Spinal cord injury that results in severe neurological disability is often incurable. The poor clinical outcome of spinal cord injury is mainly caused by the failure to reconstruct the injured neural circuits. Several intrinsic and extrinsic determinants contribute to this inability to reconnect. Epigenetic regulation acts as the driving force for multiple pathological and physiological processes in the central nervous system by modulating the expression of certain critical genes. Recent studies have demonstrated that post-SCI alteration of epigenetic landmarks is strongly associated with axon regeneration, glial activation and neurogenesis. These findings not only establish a theoretical foundation for further exploration of spinal cord injury, but also provide new avenues for the clinical treatment of spinal cord injury. This review focuses on the epigenetic regulation in axon regeneration and secondary spinal cord injury. Together, these discoveries are a selection of epigenetic-based prognosis biomarkers and attractive therapeutic targets in the treatment of spinal cord injury.

MSC-derived cytokines repair radiation-induced intra-villi microvascular injury.

Microvascular injury initiates the pathogenesis of radiation enteropathy. As previously demonstrated, the secretome from mesenchymal stem cells contains various angiogenic cytokines that exhibited therapeutic potential for ischemic lesions. As such, the present study aimed to investigate whether cytokines derived from mesenchymal stem cells can repair endothelial injuries from irradiated intestine. Here, serum-free medium was conditioned by human adipose-derived mesenchymal stem cells, and we found that there were several angiogenic cytokines in the medium, including IL-8, angiogenin, HGF and VEGF. This medium promoted the formation of tubules between human umbilical cord vein endothelial cells and protected these cells against radiation-induced apoptosis in vitro. Likewise, our in vivo results revealed that repeated injections of mesenchymal stem cell-conditioned medium could accelerate the recovery of irradiated mice by reducing the serum levels of pro-inflammatory cytokines, including IL-1α, IL-6 and TNF-α, and promoting intra-villi angiogenesis. Herein, intervention by conditioned medium could increase the number of circulating endothelial progenitors, whereas neutralizing SDF-1α and/or inhibiting PI3K would hamper the recruitment of endothelial progenitors to the injured sites. Such results suggested that SDF-1α and PI3K-mediated phosphorylation were required for intra-villi angiogenesis. To illustrate this, we found that conditioned medium enabled endothelial cells to increase intracellular levels of phosphorylated Akt Ser473, both under irradiated and steady state conditions, and to up-regulate the expression of the CXCR4 and CXCR7 genes. Collectively, the present results revealed the therapeutic effects of mesenchymal stem cell-derived cytokines on microvascular injury of irradiated intestine.

Current understanding concerning intestinal stem cells.

In mammals, the intestinal epithelium is a tissue that contains two distinct pools of stem cells: active intestinal stem cells and reserve intestinal stem cells. The former are located in the crypt basement membrane and are responsible for maintaining epithelial homeostasis under intact conditions, whereas the latter exhibit the capacity to facilitate epithelial regeneration after injury. These two pools of cells can convert into each other, maintaining their quantitative balance. In terms of the active intestinal stem cells, their development into functional epithelium is precisely controlled by the following signaling pathways: Wnt/ß-catenin, Ras/Raf/Mek/Erk/MAPK, Notch and BMP/Smad. However, mutations in some of the key regulator genes associated with these signaling pathways, such as APC, Kras and Smad4, are also highly associated with gut malformations. At this point, clarifying the biological characteristics of intestinal stem cells will increase the feasibility of preventing or treating some intestinal diseases, such as colorectal cancer. Moreover, as preclinical data demonstrate the therapeutic effects of colon stem cells on murine models of experimental colitis, the prospects of stem cell-based regenerative treatments for ulcerous lesions in the gastrointestinal tract will be improved all the same.

The anti-fibrotic effects of mesenchymal stem cells on irradiated lungs via stimulating endogenous secretion of HGF and PGE2.

Radiation-induced pulmonary fibrosis is a common disease and has a poor prognosis owing to the progressive breakdown of gas exchange regions in the lung. Recently, a novel strategy of administering mesenchymal stem cells for pulmonary fibrosis has achieved high therapeutic efficacy. In the present study, we attempted to use human adipose tissue-derived mesenchymal stem cells to prevent disease in Sprague-Dawley rats that received semi-thoracic irradiation (15 Gy). To investigate the specific roles of mesenchymal stem cells in ameliorating radiation-induced pulmonary fibrosis, we treated control groups of irradiated rats with human skin fibroblasts or phosphate-buffered saline. After mesenchymal stem cells were infused, host secretions of hepatocyte growth factor (HGF) and prostaglandin E2 (PGE2) were elevated compared with those of the controls. In contrast, tumour necrosis factor-alpha (TNF-α) and transforming growth factor-beta1 (TGF-ß1) levels were decreased after infusion of mesenchymal stem cells. Consequently, the architecture of the irradiated lungs was preserved without marked activation of fibroblasts or collagen deposition within the injured sites. Moreover, mesenchymal stem cells were able to prevent the irradiated type II alveolar epithelial cells from undergoing epithelial-mesenchymal transition. Collectively, these data confirmed that mesenchymal stem cells have the potential to limit pulmonary fibrosis after exposure to ionising irradiation.