Human skeletal stem cells (SSCs) have been discovered in fetal and adult long bones. However, the spatiotemporal ontogeny of human embryonic SSCs during early skeletogenesis remains elusive. Here we map the transcriptional landscape of human limb buds and embryonic long bones at single-cell resolution to address this fundamental question. We found remarkable heterogeneity within human limb bud mesenchyme and epithelium, and aligned them along the proximal–distal and anterior–posterior axes using known marker genes. Osteo-chondrogenic progenitors first appeared in the core limb bud mesenchyme, which give rise to multiple populations of stem/progenitor cells in embryonic long bones undergoing endochondral ossification. Importantly, a perichondrial embryonic skeletal stem/progenitor cell (eSSPC) subset was identified, which could self-renew and generate the osteochondral lineage cells, but not adipocytes or hematopoietic stroma. eSSPCs are marked by the adhesion molecule CADM1 and highly enriched with FOXP1/2 transcriptional network. Interestingly, neural crest-derived cells with similar phenotypic markers and transcriptional networks were also found in the sagittal suture of human embryonic calvaria. Taken together, this study revealed the cellular heterogeneity and lineage hierarchy during human embryonic skeletogenesis, and identified distinct skeletal stem/progenitor cells that orchestrate endochondral and intramembranous ossification.

Multipotent human adipose-derived stromal/stem cells (hADSCs) hold a great promise for cell-based therapy for many devastating human diseases, such as spinal cord injury and stroke. If exogenous hADSCs can be cultured in a three-dimensional (3D) scaffold with effective proliferation and differentiation capacity, it will better mimic the in vivo environment, which will have profound impact on the therapeutic application of hADSCs. In this study, a group of elastic-dominant, porous bioscaffolds from photocurable chitosan and gelatin were fabricated and proven to be biocompatible with both hADSCs and hADSC-derived neuron-like cells (hADSC-NLCs) in vitro. The identity of harvested hADSCs was confirmed by their positive immunostaining of mesenchymal stem cell surface markers, CD29, CD44, and CD105, and also positive expression of stem markers, Sox-2, Oct-4, c-Myc, Nanog, and Klf4. Their multipotency was further confirmed by trilineage differentiation of hADSCs toward adipocyte, osteoblast, and chondrocyte. It was found that hADSCs could be conditioned to differentiate into neurons in vitro as determined by immunostaining the markers of Tuj1, MAP2, NeuN, and Synapsin. The hADSCs and hADSC-NLCs were proven to be biocompatible with 3D scaffold, which actually facilitated the proliferation and differentiation of hADSCs in vitro, by MTT assay and their neuronal gene expression profiling. Moreover, hADSC-NLCs, which were mixed with 3D scaffold and transplanted into traumatic brain injury mouse model, survived in vivo and led to the better repair of the damaged brain area. The immunohistochemical studies revealed that 3D scaffold indeed improved the viability of transplanted cells, their ability to incorporate into the in vivo neural circuit, and their capacity for tissue repair. This study indicates that hADSCs would have great therapeutic application potential as seeding cells for in vivo transplantation to treat various neurological diseases when co-applied with porous chitosan/gelatin bioscaffolds.

In recent clinical investigations, visit-to-visit systolic blood pressure (SBP) variability was proven as a predictor of cardiovascular events and all-cause mortality. However, inconsistent results exist in this association. A meta-analysis of 13 prospective studies was conducted to evaluate the prognostic value of visit-to-visit SBP variability by different parameters in 77,299 patients with a mean follow-up of 6.3 years. The pooled age-and mean SBP-adjusted hazard ratios (HRs) for all-cause mortality were 1.03 (95% confidence interval [CI], 1.02-1.04; P<.001) per 1-mm Hg increase in SBP standard deviation (SD) and 1.04 (1.02-1.06, P<.001) per 1% in SBP coefficient of variation, and the corresponding values of cardiovascular mortality were 1.10 (1.02-1.17, P<.001) and 1.01 (0.99-1.03, P=.32), respectively. Moreover, a 1-mm Hg increase in SD was significantly associated with stroke, with an HR of 1.02 (1.01-1.03, P<.001). Visit-to-visit SBP variability, independent of age and mean SBP, is a predictor of cardiovascular and all-cause mortality and stroke.

Leptin receptor (LepR)-positive cells are key components of the bone marrow hematopoietic microenvironment, and highly enrich skeletal stem and progenitor cells that maintain homeostasis of the adult skeleton. However, the heterogeneity and lineage hierarchy within this population has been elusive. Using genetic lineage tracing and single-cell RNA sequencing, we found that Lepr-Cre labels most bone marrow stromal cells and osteogenic lineage cells in adult long bones. Integrated analysis of Lepr-Cre-traced cells under homeostatic and stress conditions revealed dynamic changes of the adipogenic, osteogenic, and periosteal lineages. Importantly, we discovered a Notch3 + bone marrow sub-population that is slow-cycling and closely associated with the vasculatures, as well as key transcriptional networks promoting osteo-chondrogenic differentiation. We also identified a Sca-1 + periosteal sub-population with high clonogenic activity but limited osteo-chondrogenic potential. Together, we mapped the transcriptomic landscape of adult LepR + stem and progenitor cells and uncovered cellular and molecular mechanisms underlying their maintenance and lineage specification.

BackgroundHeart failure (HF) remains a significant cause of morbidity and mortality. Multiple trials over the past several years have examined the effects of both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in the treatment of left ventricular dysfunction, both acutely after myocardial infarction and in chronic heart failure. Yet, there is still confusion regarding the relative efficacy of rennin-angiotensin-aldosterone system (RAAS) inhibition. Our study was conducted to assess efficacy of ACEIs and ARBs in reducing all-cause and cardiovascular mortality in heart failure patients.MethodsWe included randomized clinical trials compared ACEIs and ARBs treatment (any dose or type) with placebo treatment, no treatment, or other anti-HF drugs treatment, reporting cardiovascular or total mortality with an observation period of at least 12 months. Data sources included Pubmed, EMBASE, the Cochrane Central Register of Controlled Trials. Dichotomous outcome data from individual trials were analyzed using the risk ratio measure and its 95%CI with random-effects/ fixed-effects models. We performed meta-regression analyses to identify sources of heterogeneity. All-cause mortality and CV mortality were thought to be the main outcomes.ResultsA total of 47,662 subjects were included with a mean/median follow-up ranged from 12 weeks to 4.5 years. Of all 38 studies, 32 compared ACEIs with control therapy (included 13 arms that compared ACEIs with placebo, 10 arms in which the comparator was active treatment and 9 arms that compared ACEIs with ARBs), and six studies compared ARBs with placebo. ACEIs treatment in patients with HF reduced all-cause mortality to 11% (risk ratio (RR): 0.89, 95% confidence interval (CI): 0.83–0.96, p = 0.001) and the corresponding value for cardiovascular mortality was 14% (RR: 0.86, 95% CI: 0.78–0.94, p = 0.001). However, ARBs had no beneficial effect on reducing all-cause and cardiovascular mortality. In head-to-head analysis, ACEIs was not superior to ARBs for all-cause mortality and cardiovascular deaths.ConclusionsIn HF patients, ACEIs, but not ARBs reduced all-cause mortality and cardiovascular deaths. Thus, ACEIs should be considered as first-line therapy to limit excess mortality and morbidity in this population.Electronic supplementary materialThe online version of this article (10.1186/s12872-017-0686-z) contains supplementary material, which is available to authorized users.

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Aims The H 2 FPEF score is a convenient risk stratification tool for diagnosing heart failure with preserved ejection fraction (HFpEF). This study examined the value of the H 2 FPEF score for predicting all-cause mortality and rehospitalization in HFpEF patients. Methods and results This was a retrospective cohort study of patients diagnosed with HFpEF by echocardiography at a single tertiary centre between 1 January 2015 and 30 April 2018. According to the H 2 FPEF score, the subjects were divided into low (0-1 points), intermediate (2-5 points), and high (6-9 points) score groups. The primary outcomes were all-cause mortality and rehospitalization. A total of 476 patients (mean age: 70.5 ± 8.4 years, 60.7% female) were included. Of these, 47 (9.9%), 262 (55.0%), and 167 (35.1%) were classified into the low, intermediate, and high score groups, respectively. Over a mean follow-up of 27.5 months, 63 patients (13.2%) died, and 311 patients (65.3%) were rehospitalized. The mortality rates were 3 (6.4%), 29 (11.1%), and 31 (18.6%), and the number of patients with rehospitalization was 28 (59.6%), 159 (60.7%), and 124 (74.3%) for the low, intermediate, and high score groups, respectively. Multivariate Cox regression identified H 2 FPEF score as an independent predictor of all-cause mortality (hazard ratio [HR]: 1.46, 95% CI: 1.23-1.73, P < 0.0001) and rehospitalization (HR: 1.15, 95% CI: 1.08-1.22, P < 0.0001). Receiver operating characteristic (ROC) analysis demonstrated the H 2 FPEF score can effectively predict all-cause mortality (AUC 0.67, 95% CI: 0.60-0.73, P < 0.0001) and rehospitalization (AUC 0.59, 95% CI: 0.54-0.65, P = 0.001) after adjusting for age and NYHA class. With a cutoff value of 5.5, the sensitivity and specificity were 68.3% and 55.4% for all-cause mortality and 50.5% and 66.7% for rehospitalization. Conclusions The H 2 FPEF score can be used to predict prognosis in HFpEF patients. Higher scores are associated with higher all-cause mortality and rehospitalization.

The small intestine generally transports dietary fats to circulation in triglyceride (TG)‐rich lipoproteins. The two main intestinal lipoproteins are chylomicron (CM) and very low‐density lipoprotein (VLDL). Unfortunately, studies on the CM biogenesis and intestinal transport of dietary fats have been hampered by the lack of an adequate in vitro model. In this study, we investigated the possible factors that might increase the efficiency of CM production by Caco‐2 cells. We utilized sequential NaCl gradient ultracentrifugation to isolate the CMs that were secreted by the Caco‐2 cells. To confirm the successful isolation of the CMs, we performed Fat Red 7B staining, TG reading, apolipoprotein B (ApoB) measurement, and transmission electron microcopy (TEM) analysis. We then tested the effects of cell differentiation, oleic acid, mono‐olein, egg lecithin, incubation time, and collagen matrix on CM secretion. We found that cell differentiation, oleic acid, and lecithin were critical for CM secretion. Using the Transwell system, we further confirmed that the CMs produced by our Caco‐2 cells contained significant amount of TGs and ApoB‐48 such that they could be detected without the use of isotope labeling. In conclusion, when fully differentiated Caco‐2 were challenged with oleic acid, lecithin, and sodium taurocholate, 21% of their total number of lipoproteins were CMs with the diameter of 80–200 nm.