Comparison studies identify mesenchymal stromal cells with potent regenerative activity in osteoarthritis treatment.

Osteoarthritis affects 15% of people over 65 years of age. It is characterized by articular cartilage degradation and inflammation, leading to joint pain and disability. Osteoarthritis is incurable and the patients may eventually need joint replacement. An emerging treatment is mesenchymal stromal cells (MSCs), with over two hundred clinical trials being registered. However, the outcomes of these trials have fallen short of the expectation, due to heterogeneity of MSCs and uncertain mechanisms of action. It is generally believed that MSCs exert their function mainly by secreting immunomodulatory and trophic factors. Here we used knee osteoarthritis mouse model to assess the therapeutic effects of MSCs isolated from the white adipose or dermal adipose tissue of Prrx1-Cre; R26tdTomato mice and Dermo1-Cre; R26tdTomato mice. We found that the Prrx1-lineage MSCs from the white adipose tissues showed the greatest in vitro differentiation potentials among the four MSC groups and single cell profiling showed that the Prrx1-lineage MSCs contained more stem cells than the Dermo1 counterpart. Only the Prrx1-lineage cells isolated from white adipose tissues showed long-term therapeutic effectiveness on early-stage osteoarthritis models. Mechanistically, Prrx1-lineage MSCs differentiated into Col2+ chondrocytes and replaced the damage cartilage, activated Col1 expressing in resident chondrocytes, and inhibited synovial inflammation. Transcriptome analysis showed that the articular chondrocytes derived from injected MSCs expressed immunomodulatory cytokines, trophic factors, and chondrocyte-specific genes. Our study identified a MSC population genetically marked by Prrx1 that has great multipotentiality and can differentiate into chondrocytes to replace the damaged cartilage.

A Natural Peptide from A Traditional Chinese Medicine Has the Potential to Treat Chronic Atrophic Gastritis by Activating Gastric Stem Cells.

Chronic atrophic gastritis (AG) is initiated mainly by Helicobacter pylori infection, which may progress to stomach cancer following the Correa's cascade. The current treatment regimen is H. pylori eradication, yet evidence is lacking that this treatment is effective on later stages of AG especially gastric gland atrophy. Here, using AG mouse model, patient samples, gastric organoids, and lineage tracing, this study unraveled gastric stem cell (GSC) defect as a crucial pathogenic factor in AG in mouse and human. Moreover, a natural peptide is isolated from a traditional Chinese medicine that activated GSCs to regenerate gastric epithelia in experimental AG models and revitalized the atrophic gastric organoids derived from patients. It is further shown that the peptide exerts its functions by stabilizing the EGF-EGFR complex and specifically activating the downstream ERK and Stat1 signaling. Overall, these findings advance the understanding of AG pathogenesis and open a new avenue for AG treatment.

The processes and transport fluxes of land-based macroplastics and microplastics entering the ocean via rivers.

Approximately 80% of marine plastic waste originates from land-based sources and enters oceans through rivers. Hence, to create effective regulations, it is crucial to thoroughly examine the processes by which land-based plastic waste flows into marine environments. To this end, this review covers the complete journey of macro- and microplastics from their initial input into rivers to their ultimate release into oceans. Here, we also discuss the primary influencing factors and current popular research topics. Additionally, the principles, applicability, accuracy, uncertainty, and potential improvement of the standard methods used for flux estimation at each stage are outlined. Emission estimates of land-based macro- and microplastics are typically assessed using the emission factor approach, coefficient accounting approach, or material flow analysis. Accurately estimating mismanaged plastic waste is crucial for reducing uncertainty in the macroplastic emission inventory. In our review of the processes by which land-originating plastics enter rivers, we categorized them into two major types: point-source and diffuse-source pollution. Land surface hydrological models simulate transport from diffuse sources to rivers, necessitating further research. Riverine (micro)plastic flux to the ocean is often estimated using monitoring statistics and watershed hydrological models at the watershed scale; however, standardized monitoring methods have not yet been established. At the global scale, algorithms based on river datasets are often used, which require further improvements in river data selection and microplastic number-mass conversion factors. Furthermore, the article summarizes the accuracy and sources of uncertainty of various methods. Future research efforts should focus on quantifying and mitigating uncertainties in resultant projections. Overall, this review deepens our understanding of the processes by which land-based plastic waste enters the ocean and helps scholars efficiently select or improve relevant methods when studying land-ocean transport fluxes.

A decadal atmospheric ammonia reanalysis product in China.

Atmospheric ammonia has great environmental implications due to its important role in ecosystem and nitrogen cycle, as well as contribution to formation of secondary particles. China is recognized as a hotspot of NH3 pollution owing to agricultural and livestock intensification. In the quest to achieve a comprehensive understanding of atmospheric ammonia load and to quantify its environmental impacts in China, relying solely either on existing measurements or on model simulations falls short. Their limitations, either in spatial coverage and integrity or in data quality, fails to meet the needs. Available reanalysis products exhibit a marked deficiency in ammonia data. We therefore aim to propose an integrated ammonia reanalysis product in China, adeptly melding satellite observations from the Infrared Atmospheric Sounding Interferometer (IASI) NH3 retrievals with chemical transport model simulation, capitalizing on the robust Ensemble Kalman Filter (EnKF) data assimilation methodology. The product is validated in high quality via the comparison against independent measurements from ground monitoring stations. Spanning a decade from 2013 to 2022, our reanalysis uncovers not just the spatial intricacies of NH3 concentrations but also their temporal dynamics. Our findings pinpointed the spatial disparities in atmospheric ammonia intensities, highlighting regional hotspots in the NCP, SCB, and Northeast China, and identified annual and seasonal patterns. Our research provides crucial insights for shaping future NH3 pollution prevention and control strategies in China.

Atmospheric HONO emissions in China: Unraveling the spatiotemporal patterns and their key influencing factors.

Nitrous acid (HONO) can be photolyzed to produce hydroxyl radicals (OH) in the atmosphere. OH plays a critical role in the formation of secondary pollutants like ozone (O3) and secondary organic aerosols (SOA) via various oxidation reactions. Despite the abundance of recent HONO studies, research on national HONO emissions in China remains relatively limited. Therefore, this study employed a "wetting-drying" model and bottom-up approach to develop a high-resolution gridded inventory of HONO emissions for mainland China using multiple data. We used the Monte Carlo method to estimate the uncertainty in HONO emissions. In addition, the primary sources of HONO emissions were identified and their spatiotemporal distribution and main influencing factors were studied. The results indicated that the total HONO emissions in mainland China in 2016 were 0.77 Tg N (R50: 0.28-1.42 Tg N), with soil (0.42 Tg N) and fertilization (0.26 Tg N) as the primary sources, jointly contributing to over 87% of the total. Notably, the North China Plain (NCP) had the highest HONO emission density (3.51 kg N/ha/yr). Seasonal HONO emissions followed the order: summer (0.38 kg N/ha) > spring (0.19 kg N/ha) > autumn (0.17 kg N/ha) > winter (0.06 kg N/ha). Moreover, HONO emissions were strongly correlated with fertilization, cropland, temperature, and precipitation. This study provides vital scientific groundwork for the atmospheric nitrogen cycle and the formation of secondary pollutants.

Stromal BMP signaling regulates mucin production in the large intestine via interleukin-1/17.

Bone morphogenic protein (BMP) signaling is critical for intestinal development, homeostasis, and function performance. Although the function of BMP signaling in the intestinal epithelium is well appreciated, the direct effect of BMP on intestinal stromal cells is poorly understood. Here, we show that disruption of BMP signaling by genetic ablation of Alk3 or Smad4 expands the stromal cell pool, the mucosa tumefaction, and colonic polyposis in the large intestine. Interleukin (IL) secretion by stromal cells is notably increased, including IL-1, IL-11, and IL-17. Specifically, IL-1 and IL-17a hyperactivate the mucin production by goblet cells through nuclear factor κB signaling, and abnormal mucin accumulation results in the morphological changes, epithelial barrier destruction, and polyposis development. Together, our results provide an insight into the role of BMP signaling in intestinal stromal cells to regulate epithelium function. This study further highlights the role of mucin-producing goblet cells in intestinal homeostasis and colitis development.

The cyclooxygenase-expressing mesenchyme resists intestinal epithelial injury by paracrine signaling.

Paracrine signals play pivotal roles in organ homeostasis. Mesenchymal stromal cells (MSCs) play a key role in regulating epithelium homeostasis in the intestine while their paracrine effects are poorly characterized. Here, we identified prostaglandin E2 (PGE2) secreted by cyclooxygenase (COX)-expressing MSCs as a vital factor to maintain the intestinal mucosal barrier. We found that MSCs-induced organoid swelling through paracrine effect in vitro, a process due to enhanced water adsorption and is mediated by the COX-PGE2-EP4 axis. To further explore the regulatory effect of this axis on the intestinal epithelial barrier in vivo, we established the conditional knockout mouse model to specifically delete COX in MSCs and found that PGE2 reduction downregulated the gene Muc2 and induced a gastric metaplasia-like phenotype. Moreover, PGE2 defects increased the susceptibility of intestinal epithelium to colitis. Our study uncovers the paracrine signaling of COX-expressing MSCs in intestinal mucosal barrier maintenance, providing a basis for understanding the role of mesenchymal cells in the pathophysiological function of the intestine.

A stromal lineage maintains crypt structure and villus homeostasis in the intestinal stem cell niche.

BACKGROUND: The nutrient-absorbing villi of small intestines are renewed and repaired by intestinal stem cells (ISCs), which reside in a well-organized crypt structure. Genetic studies have shown that Wnt molecules secreted by telocytes, Gli1+ stromal cells, and epithelial cells are required for ISC proliferation and villus homeostasis. Intestinal stromal cells are heterogeneous and single-cell profiling has divided them into telocytes/subepithelial myofibroblasts, myocytes, pericytes, trophocytes, and Pdgfralow stromal cells. Yet, the niche function of these stromal populations remains incompletely understood. RESULTS: We show here that a Twist2 stromal lineage, which constitutes the Pdgfralow stromal cell and trophocyte subpopulations, maintains the crypt structure to provide an inflammation-restricting niche for regenerating ISCs. Ablating Twist2 lineage cells or deletion of one Wntless allele in these cells disturbs the crypt structure and impairs villus homeostasis. Upon radiation, Wntless haplo-deficiency caused decreased production of anti-microbial peptides and increased inflammation, leading to defective ISC proliferation and crypt regeneration, which were partially rescued by eradication of commensal bacteria. In addition, we show that Wnts secreted by Acta2+ subpopulations also play a role in crypt regeneration but not homeostasis. CONCLUSIONS: These findings suggest that ISCs may require different niches for villus homeostasis and regeneration and that the Twist2 lineage cells may help to maintain a microbe-restricted environment to allow ISC-mediated crypt regeneration.

Correlation investigation between a single nucleotide polymorphism in ADAMTS14 (rs4747096) and osteoarthritis: a meta-analysis.

BACKGROUND: Current evidence of the association between a single nucleotide polymorphism (SNP) in ADAMTS14 (rs4747096) and osteoarthritis (OA) is controversial. This study aimed to determine whether the ADAMTS14 SNP is closely related to OA risk. METHODS: An electronic search of for the association between the rs4747096 polymorphisms and OA was performed using four online databases (updated on September 10, 2022). The association between susceptibility to OA and rs4747096 polymorphism was evaluated in four genetic models: the allele (mutation [A] vs. wild type [G]), additive (AA vs. GG and AG vs. GG), recessive (AA vs. AG + GG), and dominant (AA + AG vs. GG). This meta-analysis was performed in the R software, and effects were assessed using odds ratios (ORs) and 95% confidence intervals (CI). RESULTS: Four studies (707 cases in the case group and 859 cases in the control group) were included. The results of the meta-analysis showed that, except in the recessive genetic model, there was a significant correlation between OA risk and the rs4747096 polymorphism using the allele (OR [95% CI] = 1.48 [1.26-1.73], P < 0.001), additive (AG vs. GG, OR [95% CI] = 2.56 [1.79-3.65], P < 0.001; AA vs. GG, OR [95% CI] = 2.81 [1.98-3.98], P < 0.001), and dominant (OR [95% CI)] = 1.72 [1.34-2.2], P < 0.001) genetic models. CONCLUSIONS: The ADAMTS14 rs4747096 polymorphism is associated with susceptibility to OA.

Improved ammonia emission inventory of fertilizer application for three major crops in China based on phenological data.

NH3 has an important impact on atmospheric chemistry, and its reduction has become a potential pathway to alleviate haze pollution. The existing NH3 emission inventories still have significant uncertainties in terms of their temporal distributions. In this study, we combined satellite remote-sensing phenological data with ground-station phenological data to develop a method for the temporal allocation of NH3 emissions from fertilizer application. A high-resolution dataset for fertilizer application in China was established. We developed NH3 emission inventories for the fertilization of three major crops in China, with a resolution of 1/12° × 1/12°. The results showed that there was a significant temporal variation in fertilizer application dates across the country, mainly concentrated in June (17.16 %), July (19.08 %), and August (18.77 %). The majority of fertilizer application for the three major crops occurred during the spring and summer months, with a particular emphasis on April (5.72 Tg), May (7.05 Tg), and June (4.29 Tg). The total NH3 emission from the three major crops in China in 2019 was 2.73 Tg. The North China Plain (762.23 Gg) and Middle and Lower Yangtze River Plain (606.85 Gg) were identified as the primary regions for high NH3 emissions from fertilizer application. The results also showed that NH3 emissions from the three major crops were predominantly observed during summer, with a peak value in July (606.99 Gg), mainly because of the high proportion of topdressing fertilizers. Areas with high fertilizer application generally coincided with areas of high NH3 emissions. This study may be the first to utilize remote-sensing phenological data to establish the NH3 emission inventory, which is of great significance for further improving the accuracy of the NH3 emission inventory.

Mechanisms of Si-Wu Decoction in the treatment of ulcerative colitis revealed by network pharmacology and experimental verification.

ETHNOPHARMACOLOGICAL RELEVANCE: Si-Wu Decoction (SWD) is a traditional Chinese medicine decoction. SWD is commonly used to treat blood deficiency syndrome. It is also used to treat some ulcerative colitis (UC) patients now, but the mechanism of action remains unclear. AIM OF THE STUDY: This study explored the efficacy and mechanism of action of SWD in treating UC based on network pharmacology and related experimental validation. MATERIALS AND METHODS: Several databases were used to screen SWD for major active ingredients, targets of the ingredients, and UC disease genes. Cytoscape 3.8.2 software was used for topological analysis to construct the drug-compound-disease gene-target relationship network. The String database platform was used to construct the target protein interaction network. The DAVID (Database for Annotation, Visualization and Integrated Discovery) database was used to perform the GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis for the key targets. DSS (Dextran Sulfate Sodium)-induced UC mouse model was used to evaluate the in-vivo activity of SWD. Western Blot analysis and quantitative polymerase chain reaction were performed to verify the targets in the related pathways. RESULTS: Network pharmacology revealed that the SWD targeted pathway network involved 12 core targets and 15 major pathways. SWD may play a part by targeting key targets such as nuclear factor-kappaB (NF-κB), Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) pathway, and several mitogenic pathways. We showed that SWD largely restored the colorectal structure in UC model mice. Compared to the model group, the SWD group showed reduced infiltration of inflammatory cells. SWD significantly decreased the mRNA levels of IL-6 (Interleukin-6), TNF-α (Tumor necrosis factor-alpha), IL-1b (Interleukin-1beta) and other pro-inflammatory factors. Western Blot results showed that SWD concentration-dependently inhibited STAT3 and NF-κB activation in DSS-treated colon tissue. CONCLUSION: Our findings suggest that SWD treats UC by inhibiting STAT3 and NF-κB signaling pathways, reducing the expression of inflammatory cytokines, and improving epithelial repair in experimental colitis, thus shedding light on the mechanisms by which SWD exerts its effects on UC.

ELMO1 Deficiency Reduces Neutrophil Chemotaxis in Murine Peritonitis.

Peritoneal inflammation remains a major cause of treatment failure in patients with kidney failure who receive peritoneal dialysis. Peritoneal inflammation is characterized by an increase in neutrophil infiltration. However, the molecular mechanisms that control neutrophil recruitment in peritonitis are not fully understood. ELMO and DOCK proteins form complexes which function as guanine nucleotide exchange factors to activate the small GTPase Rac to regulate F-actin dynamics during chemotaxis. In the current study, we found that deletion of the Elmo1 gene causes defects in chemotaxis and the adhesion of neutrophils. ELMO1 plays a role in the fMLP-induced activation of Rac1 in parallel with the PI3K and mTORC2 signaling pathways. Importantly, we also reveal that peritoneal inflammation is alleviated in Elmo1 knockout mice in the mouse model of thioglycollate-induced peritonitis. Our results suggest that ELMO1 functions as an evolutionarily conserved regulator for the activation of Rac to control the chemotaxis of neutrophils both in vitro and in vivo. Our results suggest that the targeted inhibition of ELMO1 may pave the way for the design of novel anti-inflammatory therapies for peritonitis.

Atmospheric ammonia in China: Long-term spatiotemporal variation, urban-rural gradient, and influencing factors.

In recent years, atmospheric ammonia (NH3) concentrations have increased in China. Ammonia control has become one of the next hot topics in air pollution mitigation with the increasing cost of acid gas emission reduction. In this study, using Infrared Atmospheric Sounding Interferometer (IASI) satellite observations, we analyzed the spatiotemporal distribution, the urban-rural gradient of the vertical column densities (VCDs) of NH3 and the contribution of influencing factors (meteorology, social, atmospheric acid gases, and NH3 emissions) in China from 2008 to 2019 using hotspot analysis, circular gradient analysis, geographical and temporal weighted regression, and some other methods. Our results showed that NH3 VCDs in China have significantly increased (31.88 %) from 2008 to 2019, with the highest occurring in North China Plain. The average NH3 VCDs in urban areas were significantly higher than those in rural areas, and the urban-rural gap in NH3 VCDs was widening. The results of circular gradient analysis showed an overall decreasing trend in NH3 VCDs along the urban-rural gradient. We used a geographically and temporally weighted regression model to analyze the contribution of various influencing factors to NH3 VCDs: meteorology (30.13 %), social (27.40 %), atmospheric acid gases (23.20 %), and NH3 emissions (19.28 %) factors. The results showed substantial spatiotemporal differences in the influencing factors. Atmospheric acid gas was the main reason for the increase in NH3 VCDs from 2008 to 2019. A more thorough understanding of the spatiotemporal distribution, urban-rural variations, and factors influencing NH3 in China will aid in developing control strategies to reduce PM2.5.

Atmospheric benzo[a]pyrene in the Yangtze River Delta, China: pollution level and lung cancer risk in 2016 and future predictions.

The Yangtze River Delta (YRD) has undergone widespread polycyclic aromatic hydrocarbon (PAH) pollution. In this study, we simulated the spatial distribution of atmospheric benzo[a]pyrene (BaP, the most carcinogenic PAH) in the YRD in 2016 and 2030 under different emission scenarios using a 3-D atmospheric transport model and evaluated the lung cancer risks posed by BaP during the study years. The purpose of this study is to suggest targeted policy recommendations for policy-makers to mitigate BaP pollution through numerical simulation. Our results showed that the average BaP concentration in the YRD was 0.30 ng/m3 in 2016; however, a significant spatial variation was observed, with the highest BaP concentration in Shanghai (0.59 ng/m3). The population-weighted incremental lifetime lung cancer risk (PILCR) was 6.67 × 10-6 in 2016, whereas it ranged from 2.70 × 10-6 to 1.05 × 10-5 in 2030 under the five emission scenarios. A higher future population density in the YRD region could increase lung cancer risk. In all scenarios, Shanghai had the highest number of lung cancer cases (range: 208-476). The results suggest that BaP pollution could be effectively improved through the synergistic effect of reducing activity levels and improving technology. Finally, we provide specific suggested pollution control strategies (e.g., accelerating the use of clean energy in rural areas) for atmospheric BaP in the YRD.

Long-term spatiotemporal variation and lung cancer risk of atmospheric polycyclic aromatic hydrocarbons (PAHs) in the Yangtze River Delta, China.

The Yangtze River Delta (YRD), which is the most developed region in China, suffers from atmospheric polycyclic aromatic hydrocarbons (PAH) pollution. However, the long-term spatiotemporal variation of atmospheric PAHs and the lung cancer risk caused by PAH exposure in the YRD remain unclear. Herein, we simulated the daily atmospheric concentration of benzo[a]pyrene (BaP, the most carcinogenic PAH) from 2001 to 2016 using an atmospheric transport model. During this period, the atmospheric BaP concentration showed a general trend of first increasing and then decreasing (average BaP concentration = 0.50 ± 0.12 ng/m3) and was highest in 2005 (0.72 ng/m3). Moreover, the BaP concentration in Jiangsu and Shanghai was 5.17- and 4.98-fold higher than that in Zhejiang. BaP pollution was severe in Jiangsu during the winter. The average area proportion of BaP exceeding the national standard in winter in Jiangsu was 69.09%. The population-weighted incremental lifetime cancer risk from 2001 to 2016 ranged 6.67 × 10-6-1.50 × 10-5, and the excess lung cancer cases ranged 1054-2130. Compared with 2005, excess lung cancer cases in the YRD decreased by 49.49% in 2016. Reducing BaP pollution in winter in Jiangsu is crucial for reducing lung cancer risk in the YRD.

Changes in PM2.5-related health burden in China's poverty and non-poverty areas during 2000-2020: A health inequality perspective.

China suffers from severe PM2.5 pollution that has resulted in a huge health burden. Such PM2.5-related health burden has long been suspected to differ between China's poverty-stricken areas (PAs) and non-poverty-stricken areas (NPAs). Yet, evidence-based examination of this long-held belief, which is critical as a barrier of environmental injustice to advancing China's sustainability, is still missing. Here our study shows that the PM2.5 pollution is more serious in China's NPAs than PAs-with their annual averages being respectively 54.83 µg/m3 and 43.63 µg/m3-causing higher premature mortality in the NPAs. Compared to economic inequality, China's total PM2.5-related premature mortality was relatively evenly distributed during 2000-2015 across regions of varying levels of gross domestic product (GDP) per capita but increased slightly in 2015-2020 owing to the dramatic change in age structure. The elderly population increased by 31 %. PM2.5-related premature deaths were more severe for populations of low socioeconomic status, and such environmental health inequalities could be amplified by population aging. Additionally, population migration from China's PAs to developed cities contributed to 638, 779, 303, 954, and 896 premature deaths in 2000, 2005, 2010, 2015, and 2020, respectively. Changes in the age structure (53 %) and PM2.5 concentration (28 %) had the greatest impact on premature deaths, followed by changes in population (12 %) and baseline mortality (8 %). The contribution rate of changes in the age structure and PM2.5 concentration was higher in PAs than in NPAs. Our findings provide insight into PM2.5-related premature death and environmental inequality, and may inform more equitable clean air policies to achieve China's sustainable development goals.

Characteristics of the gut microbiota of patients with symptomatic carotid atherosclerotic plaques positive for bacterial genetic material.

Background: The gut microbiota (GM) is believed to be closely associated with symptomatic carotid atherosclerosis (SCAS), yet more evidence is needed to substantiate the significant role of GM in SCAS. This study, based on the detection of bacterial DNA in carotid plaques, explores the characteristics of GM in SCAS patients with plaque bacterial genetic material positivity, aiming to provide a reference for subsequent research. Methods: We enrolled 27 healthy individuals (NHF group) and 23 SCAS patients (PFBS group). We utilized 16S rDNA V3-V4 region gene sequencing to analyze the microbiota in fecal samples from both groups, as well as in plaque samples from the carotid bifurcation extending to the origin of the internal carotid artery in all patients. Results: Our results indicate significant differences in the gut microbiota (GM) between SCAS patients and healthy individuals. The detection rate of bacterial DNA in plaque samples was approximately 26%. Compared to patients with negative plaques (PRSOPWNP group), those with positive plaques (PRSOPWPP group) exhibited significant alterations in their GM, particularly an upregulation of 11 bacterial genera (such as Klebsiella and Streptococcus) in the gut, which were also present in the plaques. In terms of microbial gene function prediction, pathways such as Fluorobenzoate degradation were significantly upregulated in the GM of patients with positive plaques. Conclusion: In summary, our study is the first to identify significant alterations in the gut microbiota of patients with positive plaques, providing crucial microbial evidence for further exploration of the pathogenesis of SCAS.

Prrx1 marks stem cells for bone, white adipose tissue and dermis in adult mice.

Specialized connective tissues, including bone and adipose tissues, control various physiological activities, including mineral and energy homeostasis. However, the identity of stem cells maintaining these tissues throughout adulthood remains elusive. By conducting genetic lineage tracing and cell depletion experiments in newly generated knock-in Cre/CreERT2 lines, we show here that rare Prrx1-expressing cells act as stem cells for bone, white adipose tissue and dermis in adult mice, which are indispensable for the homeostasis and repair of these tissues. Single-cell profiling reveals the cycling and multipotent nature of Prrx1-expressing cells and the stemness of these cells is further validated by transplantation assays. Moreover, we identify the cell surface markers for Prrx1-expressing stem cells and show that the activities of these stem cells are regulated by Wnt signaling. These findings expand our knowledge of connective tissue homeostasis/regeneration and may help improve stem-cell-based therapies.

Berberine increases stromal production of Wnt molecules and activates Lgr5+ stem cells to promote epithelial restitution in experimental colitis.

BACKGROUND: Inflammatory bowel diseases (IBDs) are characterized by sustained inflammation and/or ulcers along the lower digestive tract, and have complications such as colorectal cancer and inflammation in other organs. The current treatments for IBDs, which affect 0.3% of the global population, mainly target immune cells and inflammatory cytokines with a success rate of less than 40%. RESULTS: Here we show that berberine, a natural plant product, is more effective than the frontline drug sulfasalazine in treating DSS (dextran sulfate sodium)-induced colitis in mice, and that berberine not only suppresses macrophage and granulocyte activation but also promotes epithelial restitution by activating Lgr5+ intestinal stem cells (ISCs). Mechanistically, berberine increases the expression of Wnt genes in resident mesenchymal stromal cells, an ISC niche, and inhibiting Wnt secretion diminishes the therapeutic effects of berberine. We further show that berberine controls the expression of many circadian rhythm genes in stromal cells, which in turn regulate the expression of Wnt molecules. CONCLUSIONS: Our findings suggest that berberine acts on the resident stromal cells and ISCs to promote epithelial repair in experimental colitis and that Wnt-ß-Catenin signaling may be a potential target for colitis treatment.