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Chemotherapy was conventionally applied to kill cancer cells, but regrettably, they also induce damage to normal cells with high-proliferative capacity resulting in cardiotoxicity, nephrotoxicity, peripheral nerve toxicity, and ovarian toxicity. Of these, chemotherapy-induced ovarian damages mainly include but are not limited to decreased ovarian reserve, infertility, and ovarian atrophy. Therefore, exploring the underlying mechanism of chemotherapeutic drug-induced ovarian damage will pave the way to develop fertility-protective adjuvants for female patients during conventional cancer treatment. Herein, we firstly confirmed the abnormal gonadal hormone levels in patients who received chemotherapy and further found that conventional chemotherapeutic drugs (cyclophosphamide, CTX; paclitaxel, Tax; doxorubicin, Dox and cisplatin, Cis) treatment significantly decreased both the ovarian volume of mice and the number of primordial and antral follicles and accompanied with the ovarian fibrosis and reduced ovarian reserve in animal models. Subsequently, Tax, Dox, and Cis treatment can induce the apoptosis of ovarian granulosa cells (GCs), likely resulting from excessive reactive oxygen species (ROS) production-induced oxidative damage and impaired cellular anti-oxidative capacity. Thirdly, the following experiments demonstrated that Cis treatment could induce mitochondrial dysfunction through overproducing superoxide in GCs and trigger lipid peroxidation leading to ferroptosis, first reported in chemotherapy-induced ovarian damage. In addition, N-acetylcysteine (NAC) treatment could alleviate the Cis-induced toxicity in GCs by downregulating cellular ROS levels and enhancing the anti-oxidative capacity (promoting the expression of glutathione peroxidase, GPX4; nuclear factor erythroid 2-related factor 2, Nrf2 and heme oxygenase-1, HO-1). Our study confirmed the chemotherapy-induced chaotic hormonal state and ovarian damage in preclinical and clinical examination and indicated that chemotherapeutic drugs initiated ferroptosis in ovarian cells through excessive ROS-induced lipid peroxidation and mitochondrial dysfunction, leading to ovarian cell death. Consequently, developing fertility protectants from the chemotherapy-induced oxidative stress and ferroptosis perspective will ameliorate ovarian damage and further improve the life quality of cancer patients.

As a m6A methylation modifier, METTL3 is functionally involved in various biological processes. Nevertheless, the role of METTL3 in osteogenesis is not determined up to date. In the current study, METTL3 is identified as a crucial regulator in the progression of osteogenic differentiation. Loss of METTL3 significantly augments calcium deposition and enhances alkaline phosphatase activity of mesenchymal stem cells, uncovering an inhibitory role of METTL3 in osteogenesis. More importantly, the underlying molecular basis by which METTL3 regulates osteogenesis is illustrated. We find that METTL3 positively regulates expression of MYD88, a critical upstream regulator of NF-κB signaling, by facilitating m6A methylation modification to MYD88-RNA, subsequently inducing the activation of NF-κB which is widely regarded as a repressor of osteogenesis and therefore suppressing osteogenic progression. Moreover, the METTL3-mediated m6A methylation is found to be dynamically reversed by the demethylase ALKBH5. In summary, this study highlights the functional importance of METTL3 in osteogenic differentiation and METTL3 may serve as a promising molecular target in regenerative medicine, as well as in the field of bone tissue engineering.

Neurological disorders are primarily diseases with sophisticated etiology that are always refractory and recrudescent. The major obstruction to effective therapies for neurological disorders is the poor understanding of their pathogenic mechanisms. CRISPR-Cas9 technology, which allows precise and effective gene editing in almost any cell type and organism, is accelerating the pace of basic biological research. An increasing number of groups are focusing on uncovering the molecular mechanisms of neurological disorders and developing novel therapies using the CRISPR-Cas9 system. This review highlights the application of CRISPR-Cas9 technology in the treatment of neurological disorders, including Alzheimer’s disease, amyotrophic lateral sclerosis and/or frontotemporal dementia, Duchenne muscular dystrophy, Dravet syndrome, epilepsy, Huntington’s disease, and Parkinson’s disease. Hopefully, it will improve our understanding of neurological disorders and give insights into future treatments for neurological disorders.

Background Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that ultimately leads to cirrhosis and hepatocellular carcinoma. Intermittent fasting has been proposed as a nonpharmacological dietary approach against metabolic diseases, including NAFLD. In this study, we aimed to investigate the effect of alternate day fasting (ADF) on high-fat diet (HFD)-induced NAFLD in C57BL/6 mice. Methods A mouse model of fatty liver disease was established by feeding the mice a HFD for 16 weeks. The mice were administered by body weight, lipid accumulation and inflammation. PPARα, FGF21, serum triglycerides (TG), total cholesterol (TC), transaminase and lipogenesis were assessed. Results The results showed that long-term ADF can attenuate fatty liver disease by reducing hepatic inflammation and lipid accumulation in a mouse model. Meanwhile, fasting elevated the expression of serum and hepatic fibroblast growth Factor 21 (Fgf21), a circulating hormone produced predominantly in the liver, and could effectively prevent and ameliorate the pathogenesis of NAFLD. Serum starvation also enhanced Fgf21 expression and reduced free fatty acid (FFA)-induced lipid storage in hepatocytes. Moreover, refeeding inhibited the increase in Fgf21 expression induced by fasting. This fasted-to-refed transition is closely related to the expression of Fgf21. Further in vitro and in vivo studies showed that fasting-sensitive PPARα is indispensable for the expression of Fgf21 and its protective effect on NAFLD. Conclusion These findings indicated that long-term ADF protects mouse livers against HFD induced fatty liver disease through controlling PPARα/Fgf21 signaling. In conclusion, ADF can emerge as a non-pharmacological dietary approach against fatty liver disease.

Successful isolation of human endometrial stem cells from menstrual blood, namely menstrual blood‐derived endometrial stem cells (MenSCs), has provided enticing alternative seed cells for stem cell‐based therapy. MenSCs are enriched in the self‐regenerative tissue, endometrium, which shed along the periodic menstrual blood and thus their acquisition involves no physical invasiveness. However, the impact of the storage duration of menstrual blood prior to stem cell isolation, the age of the donor, the number of passages on the self‐renewing of MenSCs, the paracrine production of biological factors in MenSCs and expression of adhesion molecules on MenSCs remain elusive. In this study, we confirmed that MenSCs reside in shedding endometrium, and documented that up to 3 days of storage at 4°C has little impact on MenSCs, while the age of the donor and the number of passages are negatively associated with proliferation capacity of MenSCs. Moreover, we found that MenSCs were actually immune‐privileged and projected no risk of tumour formation. Also, we documented a lung‐ and liver‐dominated, spleen‐ and kidney‐involved organic distribution profile of MenSC 3 days after intravenous transfer into mice. At last, we suggested that MenSCs may have potentially therapeutic effects on diseases through paracrine effect and immunomodulation.

The paired box 6 ( Pax6 ) gene encodes a highly conserved transcription factor, involved in the development of eyes, brain, and endocrine glands. Homozygous loss of Pax6 resulted in neonatal death in mice, plus loss of eyes and malformation of cerebral cortex. In patients with heterozygous Pax6 mutations, a reduction in thickness of the frontoparietal cortex was detected, which was also observed in small eye mice. In this study, we found that Pax6 overexpression increased the cortical thickness, especially in the intermediate zone of the cortex, which conflicts with the report of Manuel et al. Pax6 overexpression appears to detain neurons in the intermediate zone while promoting cell proliferation. It is worth noting that the impact of Pax6 overexpression on cortical thickness and neuronal migration was temporal, explaining the differences with other reports. We postulated that the alteration of Pax6 isoform ratio by autoregulation might be responsible for this. JASPAR analysis together with the results of qPCR, Western blot, CUT&Tag, and rescue experiments revealed that Pax6 regulates neuronal migration and cell proliferation by indirectly mediating Wnt3a expression. Therefore, we propose that Pax6 participates in corticogenesis via interaction with Wnt3a in regulating neuronal migration and cell proliferation.

Background Alveolar‒capillary barrier disruption is a hallmark of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The contribution of necroptosis to the compromised alveolar-barrier in ALI remains unclear. Mesenchymal stem cells (MSCs) may contribute to tissue repair in ALI and ARDS. Here we evaluated the efficacy and explored the molecular mechanisms of menstrual blood-derived endometrial stem cells (MenSCs) and MenSC-derived extracellular vesicles (MenSC-EVs) in ALI-induced alveolar epithelial barrier dysfunction. Methods Human lung epithelial cells were stimulated with endotoxin and treated with MenSCs or MenSC-EVs, and their barrier properties were evaluated. Lipopolysaccharide (LPS)-injured mice were treated with MenSCs or MSC-EVs, and the degree of lung injury and the alveolar epithelial barrier of the lung tissue were assessed. Results We found that MenSCs reduced lung injury and restored alveolar-barrier integrity in lung tissue. In vitro, MenSCs reduced paracellular permeability and restored barrier integrity in human lung epithelial cells. MenSC-EVs replicated all these MenSC-mediated changes. Mechanistic research revealed that MenSCs inhibited MAPK signaling and necroptosis. JNK inhibition SP600125, and ERK inhibition U0126 or inhibition of necroptosis with Nec-1 or GSK872 diminished the beneficial anti-epithelial barrier dysfunction effects of MenSCs or MenSC-EVs. Conclusions Our results suggest that human menstrual blood-derived endometrial stem cells mitigate lung injury and improve alveolar barrier properties by inhibiting MAPK-mediated necroptosis through extracellular vesicles, supporting the application of MenSCs or MenSC-derived extracellular vesicles to treat ALI or ARDS.

The transcriptional repressor FOXN3 plays a key role in regulating pulmonary inflammatory responses, which are crucial in the development of pulmonary fibrosis. However, its specific regulatory function in lung fibrosis remains unclear. Here, we show that FOXN3 suppresses pulmonary fibrosis by inhibiting Smad transcriptional activity. FOXN3 targets a substantial number of Smad response gene promoters, facilitating Smad4 ubiquitination, which disrupts the association of the Smad2/3/4 complex with chromatin and abolishes its transcriptional response. In response to pro-fibrotic stimuli, NEK6 phosphorylates FOXN3 at S412 and S416, leading to its degradation. The loss of FOXN3 inhibits β-TrCP-mediated ubiquitination of Smad4, stabilizing the Smad complex’s association with its responsive elements and promoting transcriptional activation, thus contributing to the development of pulmonary fibrosis. Notably, we found a significant inverse expression pattern between FOXN3 and Smad4 in clinical pulmonary fibrosis cases, underscoring the importance of the NEK6-FOXN3-Smad axis in the pathological process of pulmonary fibrosis. This study identifies FOXN3 as a suppressor of pulmonary fibrosis by inhibiting Smad signaling. FOXN3 facilitates Smad4 ubiquitination, disrupting the Smad complex’s association with target elements and abolishing its transcriptional activity.

Chemotherapy can cause ovarian dysfunction and infertility since the ovary is extremely sensitive to chemotherapeutic drugs. Apart from the indispensable role of the ovary in the overall hormonal milieu, ovarian dysfunction also affects many other organ systems and functions including sexuality, bones, the cardiovascular system, and neurocognitive function. Although conventional hormone replacement therapy can partly relieve the adverse symptoms of premature ovarian insufficiency (POI), the treatment cannot fundamentally prevent deterioration of POI. Therefore, effective treatments to improve chemotherapy-induced POI are urgently needed, especially for patients desiring fertility preservation. Recently, mesenchymal stem cell (MSC)-based therapies have resulted in promising improvements in chemotherapy-induced ovary dysfunction by enhancing the anti-apoptotic capacity of ovarian cells, preventing ovarian follicular atresia, promoting angiogenesis and improving injured ovarian structure and the pregnancy rate. These improvements are mainly attributed to MSC-derived biological factors, functional RNAs, and even mitochondria, which are directly secreted or indirectly translocated with extracellular vesicles (microvesicles and exosomes) to repair ovarian dysfunction. Additionally, as a novel source of MSCs, menstrual blood-derived endometrial stem cells (MenSCs) have exhibited promising therapeutic effects in various diseases due to their comprehensive advantages, such as periodic and non-invasive sample collection, abundant sources, regular donation and autologous transplantation. Therefore, this review summarizes the efficacy of MSCs transplantation in improving chemotherapy-induced POI and analyzes the underlying mechanism, and further discusses the benefit and existing challenges in promoting the clinical application of MenSCs in chemotherapy-induced POI.

Stem cell-based regenerative therapies have recently become promising and advanced for treating stroke. Mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) have received the most attention for treating stroke because of the outstanding paracrine function of MSCs and the three-germ-layer differentiation ability of iPSCs. However, the unsatisfactory homing ability, differentiation, integration, and survival time in vivo limit the effectiveness of MSCs in regenerative medicine. The inherent tumorigenic property of iPSCs renders complete differentiation necessary before transplantation, which is complicated and expensive and affects the consistency among cell batches. Multilineage differentiating stress-enduring (Muse) cells are natural pluripotent stem cells in the connective tissues of nearly every organ and thus are considered nontumorigenic. A single Muse cell can differentiate into all three-germ-layer, preferentially migrate to damaged sites after transplantation, survive in hostile environments, and spontaneously differentiate into tissue-compatible cells, all of which can compensate for the shortcomings of MSCs and iPSCs. This review summarizes the recent progress in understanding the biological properties of Muse cells and highlights the differences between Muse cells and other types of stem cells. Finally, we summarized the current research progress on the application of Muse cells on stroke and challenges from bench to bedside.