Unresolved inflammation can lead to tissue fibrosis and impaired organ function. Macrophage–myofibroblast transition (MMT) is one newly identified mechanism by which ongoing chronic inflammation ...causes progressive fibrosis in different forms of kidney disease. However, the mechanisms underlying MMT are still largely unknown. Here, we discovered a brain-specific homeobox/POU domain protein Pou4f1 (Brn3a) as a specific regulator of MMT. Interestingly, we found that Pou4f1 is highly expressed by macrophages undergoing MMT in sites of fibrosis in human and experimental kidney disease, identified by coexpression of the myofibroblast marker, α-SMA. Unexpectedly, Pou4f1 expression peaked in the early stage in renal fibrogenesis in vivo and during MMT of bone marrow-derived macrophages (BMDMs) in vitro. Mechanistically, chromatin immunoprecipitation (ChIP) assay identified that Pou4f1 is a Smad3 target and the key downstream regulator of MMT, while microarray analysis defined a Pou4f1-dependent fibrogenic gene network for promoting TGF-β1/Smad3-driven MMT in BMDMs at the transcriptional level. More importantly, using two mouse models of progressive renal interstitial fibrosis featuring the MMT process, we demonstrated that adoptive transfer of TGF-β1-stimulated BMDMs restored both MMT and renal fibrosis in macrophage-depleted mice, which was prevented by silencing Pou4f1 in transferred BMDMs. These findings establish a role for Pou4f1 in MMT and renal fibrosis and suggest that Pou4f1 may be a therapeutic target for chronic kidney disease with progressive renal fibrosis.
Cancer‐associated fibroblasts (CAFs) are important in tumor microenvironment (TME) driven cancer progression. However, CAFs are heterogeneous and still largely underdefined, better understanding ...their origins will identify new therapeutic strategies for cancer. Here, the authors discovered a new role of macrophage‐myofibroblast transition (MMT) in cancer for de novo generating protumoral CAFs by resolving the transcriptome dynamics of tumor‐associated macrophages (TAM) with single‐cell resolution. MMT cells (MMTs) are observed in non‐small‐cell lung carcinoma (NSCLC) associated with CAF abundance and patient mortality. By fate‐mapping study, RNA velocity, and pseudotime analysis, existence of novel macrophage‐lineage‐derived CAF subset in the TME of Lewis lung carcinoma (LLC) model is confirmed, which is directly transited via MMT from M2‐TAM in vivo and bone‐marrow‐derived macrophages (BMDM) in vitro. Adoptive transfer of BMDM‐derived MMTs markedly promote CAF formation in LLC‐bearing mice. Mechanistically, a Smad3‐centric regulatory network is upregulated in the MMTs of NSCLC, where chromatin immunoprecipitation sequencing(ChIP‐seq) detects a significant enrichment of Smad3 binding on fibroblast differentiation genes in the macrophage‐lineage cells in LLC‐tumor. More importantly, macrophage‐specific deletion and pharmaceutical inhibition of Smad3 effectively block MMT, therefore, suppressing the CAF formation and cancer progression in vivo. Thus, MMT may represent a novel therapeutic target of CAF for cancer immunotherapy.
Here, the authors discovered a direct mechanism of tumor‐associated macrophages for de novo generating protumoral cancer‐associated fibroblasts (CAF) via macrophage‐myofibroblast transition (MMT) by resolving their transcriptome dynamics at single‐cell resolution. Encouragingly, targeting the MMT key regulator Smad3 effectively blocked the production and protumoral actions of CAF, evidencing its translational potential as a novel therapeutic target in the tumour microenvironment for cancer.
A novel theory in the field of tumor biology postulates that cancer growth is driven by a population of stem‐like cells, called tumor‐initiating cells (TICs). We previously identified a TIC ...population derived from hepatocellular carcinoma (HCC) that is characterized by membrane expression of CD133. Here, we describe a novel mechanism by which these cells mediate tumor growth and angiogenesis by systematic comparison of the gene expression profiles between sorted CD133 liver subpopulations through genome‐wide microarray analysis. A significantly dysregulated interleukin‐8 (IL‐8) signaling network was identified in CD133+ liver TICs obtained from HCC clinical samples and cell lines. IL‐8 was found to be overexpressed at both the genomic and proteomic levels in CD133+ cells isolated from HCC cell lines or clinical samples. Functional studies found enhanced IL‐8 secretion in CD133+ liver TICs to exhibit a greater ability to self‐renew, induce tumor angiogenesis, and initiate tumors. In further support of these observations, IL‐8 repression in CD133+ liver TICs by knockdown or neutralizing antibody abolished these effects. Subsequent studies of the IL‐8 functional network identified neurotensin (NTS) and CXCL1 to be preferentially expressed in CD133+ liver TICs. Addition of exogenous NTS resulted in concomitant up‐regulation of IL‐8 and CXCL1 with simultaneous activation of p‐ERK1/2 and RAF‐1, both key components of the mitogen‐activated protein kinase (MAPK) pathway. Enhanced IL‐8 secretion by CD133+ liver TICs can in turn activate an IL‐8‐dependent feedback loop that signals through the MAPK pathway. Further, in its role as a liver TIC marker CD133 also plays a functional part in regulating tumorigenesis of liver TICs by way of regulating NTS, IL‐8, CXCL1, and MAPK signaling. Conclusion: CD133+ liver TICs promote angiogenesis, tumorigenesis, and self‐renewal through NTS‐induced activation of the IL‐8 signaling cascade. (Hepatology 2012)
Src activation has been associated with fibrogenesis after kidney injury. Macrophage-myofibroblast transition is a newly identified process to generate collagen-producing myofibroblasts locally in ...the kidney undergoing fibrosis in a TGF-β/Smad3-dependent manner. The potential role of the macrophage-myofibroblast transition in Src-mediated renal fibrosis is unknown. In studying this by RNA sequencing at single-cell resolution, we uncovered a unique Src-centric regulatory gene network as a key underlying mechanism of macrophage-myofibroblast transition. A total of 501 differentially expressed genes associated with macrophage-myofibroblast transition were identified. However, Smad3-knockout largely reduced the transcriptome diversity. More importantly, inhibition of Src largely suppresses ureteral obstruction-induced macrophage-myofibroblast transition in the injured kidney in vivo along with transforming growth factor-β1-induced elongated fibroblast-like morphology, α-smooth muscle actin expression and collagen production in bone marrow derived macrophages in vitro. Unexpectedly, we further uncovered that Src serves as a direct Smad3 target gene and also specifically up-regulated in macrophages during macrophage-myofibroblast transition. Thus, macrophage-myofibroblast transition contributes to Src-mediated tissue fibrosis. Hence, targeting Src may represent as a precision therapeutic strategy for macrophage-myofibroblast transition-driven fibrotic diseases.
Objective
To evaluate the effectiveness of small‐group nurse‐administered cognitive behavioural therapy for insomnia (CBTI) as an early intervention of mood disorders with comorbid insomnia.
Methods
...A total of 200 patients with first‐episode depressive or bipolar disorders and comorbid insomnia were randomized in a ratio of 1:1 to receiving 4‐session CBTI or not in a routine psychiatric care setting. Primary outcome was Insomnia Severity Index. Secondary outcomes included response and remission status; daytime symptomatology and quality of life; medication burden; sleep‐related cognitions and behaviours; and the credibility, satisfaction, adherence and adverse events of CBTI. Assessments were conducted at baseline, 3, 6, and 12‐month.
Results
Only a significant time‐effect but no group‐by‐time interaction was found in the primary outcome. Several secondary outcomes had significantly greater improvements in CBTI group, including higher depression remission at 12‐month (59.7% vs. 37.9%, χ2 = 6.57, p = .01), lower anxiolytic use at 3‐month (18.1% vs. 33.3%, χ2 = 4.72, p = .03) and 12‐month (12.5% vs. 25.8%, χ2 = 3.26, p = .047), and lesser sleep‐related dysfunctional cognitions at 3 and 6‐month (mixed‐effects model, F = 5.12, p = .001 and .03, respectively). Depression remission rate was 28.6%, 40.3%, and 59.7% at 3, 6, and 12‐month, respectively in CBTI group and 28.4%, 31.1%, and 37.9%, respectively in no CBTI group.
Conclusion
CBTI may be a useful early intervention to enhance depression remission and reduce medication burden in patients with first‐episode depressive disorder and comorbid insomnia.
Neutrophils are dynamic with their phenotype and function shaped by the microenvironment, such as the N1 antitumor and N2 pro-tumor states within the tumor microenvironment (TME), but its regulation ...remains undefined. Here we examine TGF-β1/Smad3 signaling in tumor-associated neutrophils (TANs) in non-small cell lung carcinoma (NSCLC) patients. Smad3 activation in N2 TANs is negatively correlate with the N1 population and patient survival. In experimental lung carcinoma, TANs switch from a predominant N2 state in wild-type mice to an N1 state in Smad3-KO mice which associate with enhanced neutrophil infiltration and tumor regression. Neutrophil depletion abrogates the N1 anticancer phenotype in Smad3-KO mice, while adoptive transfer of Smad3-KO neutrophils reproduces this protective effect in wild-type mice. Single-cell analysis uncovers a TAN subset showing a mature N1 phenotype in Smad3-KO TME, whereas wild-type TANs mainly retain an immature N2 state due to Smad3. Mechanistically, TME-induced Smad3 target genes related to cell fate determination to preserve the N2 state of TAN. Importantly, genetic deletion and pharmaceutical inhibition of Smad3 enhance the anticancer capacity of neutrophils against NSCLC via promoting their N1 maturation. Thus, our work suggests that Smad3 signaling in neutrophils may represent a therapeutic target for cancer immunotherapy.
A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor, called tumor-initiating cells (TICs) or cancer stem cells (CSCs). Here we describe the ...identification and characterization of such cells from hepatocellular carcinoma (HCC) using the marker CD133. CD133 accounts for approximately 1.3%–13.6% of the cells in the bulk tumor of human primary HCC samples. When compared with their CD133
− counterparts, CD133
+ cells not only possess the preferential ability to form undifferentiated tumor spheroids in vitro but also express an enhanced level of stem cell-associated genes, have a greater ability to form tumors when implanted orthotopically in immunodeficient mice, and can be serially passaged into secondary animal recipients. Xenografts resemble the original human tumor and maintain a similar percentage of tumorigenic CD133
+ cells. Quantitative PCR analysis of 41 separate HCC tissue specimens with follow-up data found that CD133
+ tumor cells were frequently detected at low quantities in HCC, and their presence was also associated with worse overall survival and higher recurrence rates. Subsequent differential microRNA expression profiling of CD133
+ and CD133
− cells from human HCC clinical specimens and cell lines identified an overexpression of miR-130b in CD133
+ TICs. Functional studies on miR-130b lentiviral-transduced CD133
− cells demonstrated superior resistance to chemotherapeutic agents, enhanced tumorigenicity in vivo, and a greater potential for self renewal. Conversely, antagonizing miR-130b in CD133
+ TICs yielded an opposing effect. The increased miR-130b paralleled the reduced TP53INP1, a known miR-130b target. Silencing TP53INP1 in CD133
− cells enhanced both self renewal and tumorigenicity in vivo. Collectively, miR-130b regulates CD133
+ liver TICs, in part, via silencing TP53INP1.
► CD133 identifies liver TICs/CSCs and is a prognostic marker for HC ► miR-130b promotes CD133
+ liver TICs growth and self renewal ► miR-130b regulates CD133
+ liver TICs via silencing TP53INP1
The COVID-19 pandemic is a large-scale public health emergency that likely precipitated sleep disturbances in the community. This study aimed to investigate the prevalence and correlates of sleep ...disturbances during the early phase of COVID-19 pandemic.
This web-based cross-sectional study recruited 1138 Hong Kong adults using convenience sampling over a two-week period from 6th April 2020. The survey collected data on sleep disturbances, mood, stress, stock of infection control supplies, perceived risk of being infected by COVID-19, and sources for acquiring COVID-19 information. The participants were asked to compare their recent sleep and sleep before the outbreak. The Insomnia Severity Index (ISI) was used to assess their current insomnia severity. Prevalence was weighted according to 2016 population census.
The weighted prevalence of worsened sleep quality, difficulty in sleep initiation, and shortened sleep duration since the outbreak were 38.3%, 29.8%, and 29.1%, respectively. The prevalence of current insomnia (ISI score of ≥10) was 29.9%. Insufficient stock of masks was significantly associated with worsened sleep quality, impaired sleep initiation, shortened sleep duration, and current insomnia in multivariate logistic regression (adjusted OR = 1.57, 1.72, 1.99, and 1.96 respectively, all p < 0.05).
A high proportion of people in Hong Kong felt that their sleep had worsened since the COVID-19 outbreak. Insufficient stock of masks was one of the risk factors that were associated with sleep disturbances. Adequate and stable supply of masks may play an important role to maintain the sleep health in the Hong Kong general population during a pandemic outbreak.
•Around 30-40% of respondents felt their sleep worsened since the local outbreak.•The prevalence of insomnia in Hong Kong during the COVID-19 pandemic was high.•An insufficient store of masks for one-month was associated with worsening of sleep.•A stable supply of masks may play a role in sleep health during an outbreak.
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