A certain number of epithelial cells in intestinal crypts are DNA damage resistant and contribute to regeneration. However, the cellular mechanism underlying intestinal regeneration remains unclear. Using lineage tracing, we show that cells marked by an Msi1 reporter (Msi1+) are right above Lgr5high cells in intestinal crypts and exhibit DNA damage resistance. Single-cell RNA sequencing reveals that the Msi1+ cells are heterogeneous with the majority being intestinal stem cells (ISCs). The DNA damage-resistant subpopulation of Msi1+ cells is characterized by low-to-negative Lgr5 expression and is more rapidly cycling than Lgr5high radiosensitive crypt base columnar stem cells (CBCs). This enables an efficient repopulation of the intestinal epithelium at early stage when Lgr5high cells are not emerging. Furthermore, relative to CBCs, Msi1+ cells preferentially produce Paneth cells during homeostasis and upon radiation repair. Together, we demonstrate that the DNA damage-resistant Msi1+ cells are cycling ISCs that maintain and regenerate the intestinal epithelium.
Myoepithelial and luminal cells synergistically expand in the mammary gland during pregnancy, and this process is precisely governed by hormone-related signaling pathways. The bone morphogenetic protein (BMP) signaling pathway is now known to play crucial roles in all organ systems. However, the functions of BMP signaling in the mammary gland remain unclear. Here, we found that BMPR1a is upregulated by hormone-induced Sp1 at pregnancy. Using a doxycycline (Dox)-inducible BMPR1a conditional knockout mouse model, we demonstrated that loss of BMPR1a in myoepithelium results in compromised myoepithelial integrity, reduced mammary stem cells and precocious alveolar differentiation during pregnancy. Mechanistically, BMPR1a regulates the expression of p63 and Slug, two key regulators of myoepithelial maintenance, through pSmad1/5-Smad4 complexes, and consequently activate P-cadherin during pregnancy. Furthermore, we observed that loss of BMPR1a in myoepithelium results in the upregulation of a secreted protein Spp1 that could account for the precocious alveolar differentiation in luminal layer, suggesting a defective basal-to-luminal paracrine signaling mechanism. Collectively, these findings identify a novel role of BMP signaling in maintaining the identity of myoepithelial cells and suppressing precocious alveolar formation.
Abstract The +4 cells in intestinal crypts are DNA damage-resistant and contribute to regeneration. However, their exact identity and the mechanism underlying +4 cell-mediated regeneration remain unclear. Using lineage tracing, we show that cells marked by an Msi1 reporter ( Msi1 + ) are enriched at the +4 position in intestinal crypts and exhibit DNA damage resistance. Single-cell RNA sequencing reveals that the Msi1 + cells are heterogeneous with the majority being intestinal stem cells (ISCs). The DNA damage-resistant subpopulation of Msi1 + cells is characterized by low-to-negative Lgr5 expression and is more rapidly cycling than Lgr5 high radio-sensitive crypt base columnar stem cells (CBCs); they enable fast repopulation of the intestinal epithelium independent of CBCs that are largely depleted after irradiation. Furthermore, relative to CBCs, Msi1 + cells preferentially produce Paneth cells during homeostasis and upon radiation repair. Together, we demonstrate that the DNA damage-resistant Msi1 + cells are rapidly cycling ISCs that maintain and regenerate the intestinal epithelium.
Interstitial lung disease (ILD) is a group of diffuse lung diseases that mainly affect the pulmonary interstitium and alveolar space, resulting in the loss of alveolar-capillary functional units, so early diagnosis is the key to effective management of ILD.Thoracic high-resolution CT, pulmonary function tests, bronchoscopy and lung biopsy are effective means for diagnosis of ILD, and can assess disease severity and treatment efficacy.But it is costly, radiant and invasive.Studies have found that alveolar type Ⅱ cell surface antigen 6 (KL-6) is a promising serological marker for ILD, which is significantly associated with the occurrence, progression, drug efficacy and prognosis of ILD.It is also found that KL-6 also plays an important role in other respiratory diseases.This article reviews the research progress of KL-6 in respiratory diseases.
Key words:
KL-6; Lung diseases, interstitial
Rationale: Dysregulation of signaling that governs self-renewal and differentiation of intestinal stem cells (ISCs) is a major cause of colorectal cancer (CRC) initiation and progression.Methods: qRT-PCR, western blotting, in situ hybridization, immunohistochemistry and immunofluorescence assays were used to detect the expression levels of MEX3A, KLF4 and E2F3 in CRC tissues.The biological functions of MEX3A were studied using Mex3a knockout (KO) and intestinal epithelium specific conditional knockout (cKO) mice, AOM-DSS mouse colorectal tumor model, Apc floxed mouse tumor model and intestinal and tumor organoids.Transcriptomic RNA sequencing (RNA-seq), RNA crosslinking immunoprecipitation (CLIP) and luciferase reporter assays were performed to explore the molecular mechanisms of MEX3A.Results: RNA-binding protein MEX3A, a specific ISC marker gene, becomes ectopically upregulated upon CRC and its levels negatively correlate with patient survival prognosis.MEX3A functions as an oncoprotein that retains cancer cells in undifferentiated and proliferative status and it enhances their radioresistance to DNA damage.Mechanistically, a rate limiting factor of cellular proliferation E2F3 induces MEX3A, which in turn activates WNT pathway by directly suppressing expression of its pro-differentiation transcription factor KLF4. Knockdown of MEX3A with siRNA or addition of KLF4 agonist significantly suppressed tumor growth both by increasing differentiation status of cancer cells and by suppressing their proliferation.Conclusions: It identifies E2F3-MEX3A-KLF4 axis as an essential coordinator of cancer stem cell self-renewal and differentiation, representing a potent new druggable target for cancer differentiation therapy.
Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a disorder of recurrent hypoxia and daytime sleepiness caused by airway collapse during sleep.Obstructive sleep apnea-hypopnea syndrome is closely related to cardiovascular diseases such as hypertension, arrhythmia, coronary atherosclerotic heart disease and heart failure.OSAHS plays an important role in promoting the occurrence and development of cardiovascular diseases.Currently, OSAHS as an important risk factor of coronary atherosclerotic heart disease is gradually paid attention to.This article reviews the pathogenesis of OSAHS induced coronary heart disease, the relationship between OSAHS and coronary artery stenosis, the adverse prognosis of OSAHS combined with coronary heart disease and the effect of continuous positive airway pressure on the prognosis of these patients.
Key words:
Sleep apnea, obstructive; Coronary artery disease; Coronary stenosis; Continuous positive airway pressure; Pathogenesis
Combined pulmonary fibrosis and emphysema (CPFE) is currently considered to be independent disease that is apart from either emphysema or pulmonary fibrosis alone.At present, there are no clear diagnostic criteria for CPFE at home and abroad.CPFE is characterized by lower lobe fibrosis and upper lobe emphysema on chest high resolution computed tomography scans.CPFE is often associated with pulmonary hypertension, lung cancer, etc., and the prognosis is poor.It is reported that the median survival time is only 2.1-8.5 years, and there is currently no effective treatment and management.This article reviews the possible pathogenesis, clinical manifestations, pulmonary function characteristics, complications, clinical treatment and related prognosis of CPFE, in order to provide relevant bases for clinical diagnosis and treatment of CPFE.
Key words:
Pulmonary fibrosis; Lung diseases, interstitial; Pulmonary emphysema; Clinical features
Inflammatory bowel disease (IBD) is a chronic intestinal inflammation that is currently incurable. Increasing evidence indicates that supplementation with probiotics could improve the symptoms of IBD. It is scientifically significant to identify novel and valid strains for treating IBD. It has been reported that the probiotic Lactobacillus paracasei L9 (L9), which is identified from the gut of healthy centenarians, can modulate host immunity and plays an anti-allergic role. Here, we demonstrated that L9 alleviates the pathological phenotypes of experimental colitis by expanding the abundance of butyrate-producing bacteria. Oral administration of sodium butyrate in experimental colitis recapitulates the L9 anti-inflammatory phenotypes. Mechanistically, sodium butyrate ameliorated the inflammatory responses by inhibiting the IL-6/STAT3 signaling pathway in colitis. Overall, these findings demonstrated that L9 alleviates the DSS-induced colitis development by enhancing the abundance of butyrate-producing bacterial strains that produce butyrate to suppress the IL-6/STAT3 signaling pathway, providing new insight into a promising therapeutic target for the remission of IBD.
Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders caused by the disruption of immune tolerance to the gut microbiota. MicroRNA-31 (MIR31) has been proven to be up-regulated in intestinal tissues from patients with IBDs and colitis-associated neoplasias. While the functional role of MIR31 in colitis and related diseases remain elusive. Combining mathematical modeling and experimental analysis, we systematically explored the regulatory mechanism of MIR31 in inflammatory and epithelial regeneration responses in colitis. Level of MIR31 presents an "adaptation" behavior in dextran sulfate sodium (DSS)-induced colitis, and the similar behavior is also observed for the key cytokines of p65 and STAT3. Simulation analysis predicts MIR31 suppresses the activation of p65 and STAT3 but accelerates the recovery of epithelia in colitis, which are validated by our experimental observations. Further analysis reveals that the number of proliferative epithelial cells, which characterizes the inflammatory process and the recovery of epithelia in colitis, is mainly determined by the inhibition of MIR31 on IL17RA. MIR31 promotes epithelial regeneration in low levels of DSS-induced colitis but inhibits inflammation with high DSS levels, which is dominated by the competition for MIR31 to either inhibit inflammation or promote epithelial regeneration by binding to different targets. The binding probability determines the functional transformation of MIR31, but the functional strength is determined by MIR31 levels. Thus, the role of MIR31 in the inflammatory response can be described as the "spring-like effect," where DSS, MIR31 action strength, and proliferative epithelial cell number are regarded as external force, intrinsic spring force, and spring length, respectively. Overall, our study uncovers the vital roles of MIR31 in balancing inflammation and the recovery of epithelia in colitis, providing potential clues for the development of therapeutic targets in drug design.
'/%3e%3cuse xlink:href='%23a' transform='rotate(23.036 .093 25.536)'/%3e%3cuse xlink:href='%23a' transform='rotate(45.87 1.273 16.18)'/%3e%3cuse xlink:href='%23a' transform='rotate(69.945 .996 12.078)'/%3e%3cuse xlink:href='%23a' transform='rotate(20.66 -19.689 31.932)'/%3e%3c/svg%3e)
