Hypoxia-inducible factor (HIF-1α), a core transcription factor responding to changes in cellular oxygen levels, is closely associated with a wide range of physiological and pathological conditions. However, its differential impacts on vascular cell types and molecular programs modulating human vascular homeostasis and regeneration remain largely elusive. Here, we applied CRISPR/Cas9-mediated gene editing of human embryonic stem cells and directed differentiation to generate HIF-1α-deficient human vascular cells including vascular endothelial cells, vascular smooth muscle cells, and mesenchymal stem cells (MSCs), as a platform for discovering cell type-specific hypoxia-induced response mechanisms. Through comparative molecular profiling across cell types under normoxic and hypoxic conditions, we provide insight into the indispensable role of HIF-1α in the promotion of ischemic vascular regeneration. We found human MSCs to be the vascular cell type most susceptible to HIF-1α deficiency, and that transcriptional inactivation of ANKZF1, an effector of HIF-1α, impaired pro-angiogenic processes. Altogether, our findings deepen the understanding of HIF-1α in human angiogenesis and support further explorations of novel therapeutic strategies of vascular regeneration against ischemic damage.
Humans ; Vascular Endothelial Growth Factor A/metabolism* ; Endothelial Cells/metabolism* ; Transcription Factors/metabolism* ; Gene Expression Regulation ; Hypoxia/metabolism* ; Cell Hypoxia/physiology*

Progressive functional deterioration in the cochlea is associated with age-related hearing loss (ARHL). However, the cellular and molecular basis underlying cochlear aging remains largely unknown. Here, we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging, in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points. Overall, our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging, highlights unexpected age-related transcriptional fluctuations in intermediate cells localized in the stria vascularis (SV) and demonstrates that upregulation of endoplasmic reticulum (ER) chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging. Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related SV atrophy and hence delay the progression of ARHL.
Mice ; Animals ; Transcriptome ; Aging/metabolism* ; Cochlea ; Stria Vascularis ; Presbycusis

Aging poses a major risk factor for cardiovascular diseases, the leading cause of death in the aged population. However, the cell type-specific changes underlying cardiac aging are far from being clear. Here, we performed single-nucleus RNA-sequencing analysis of left ventricles from young and aged cynomolgus monkeys to define cell composition changes and transcriptomic alterations across different cell types associated with age. We found that aged cardiomyocytes underwent a dramatic loss in cell numbers and profound fluctuations in transcriptional profiles. Via transcription regulatory network analysis, we identified FOXP1, a core transcription factor in organ development, as a key downregulated factor in aged cardiomyocytes, concomitant with the dysregulation of FOXP1 target genes associated with heart function and cardiac diseases. Consistently, the deficiency of FOXP1 led to hypertrophic and senescent phenotypes in human embryonic stem cell-derived cardiomyocytes. Altogether, our findings depict the cellular and molecular landscape of ventricular aging at the single-cell resolution, and identify drivers for primate cardiac aging and potential targets for intervention against cardiac aging and associated diseases.
Aged ; Animals ; Humans ; Aging/genetics* ; Forkhead Transcription Factors/metabolism* ; Myocytes, Cardiac/metabolism* ; Primates/metabolism* ; Repressor Proteins/metabolism* ; Transcriptome ; Macaca fascicularis/metabolism*

Hair loss affects millions of people at some time in their life, and safe and efficient treatments for hair loss are a significant unmet medical need. We report that topical delivery of quercetin (Que) stimulates resting hair follicles to grow with rapid follicular keratinocyte proliferation and replenishes perifollicular microvasculature in mice. We construct dynamic single-cell transcriptome landscape over the course of hair regrowth and find that Que treatment stimulates the differentiation trajectory in the hair follicles and induces an angiogenic signature in dermal endothelial cells by activating HIF-1α in endothelial cells. Skin administration of a HIF-1α agonist partially recapitulates the pro-angiogenesis and hair-growing effects of Que. Together, these findings provide a molecular understanding for the efficacy of Que in hair regrowth, which underscores the translational potential of targeting the hair follicle niche as a strategy for regenerative medicine, and suggest a route of pharmacological intervention that may promote hair regrowth.
Mice ; Animals ; Quercetin/pharmacology* ; Endothelial Cells ; Hair ; Hair Follicle ; Alopecia

Objective:To investigate the differences in applicability of both the portable high-purity germanium (HPGe) γ spectrometer and the portable lanthanum bromide (LaBr) γ spectrometer for measuring thyroid 131I activity and internal exposure monitoring for radiation workers. Method:Both DETECTIVE-DX100-KT portable HPGe γ spectrometer and InSpector 1000 portable LaBr γ spectrometer were used to measure the 131I content in thyroid of radiation workers for comparison of the measuring result, minimum detectable activity (MDA) and corresponding annual committed effective doses between two types of spectrometers. Results:The detection rate of 131I in thyroid of radiation workers was 67.7% for HPGe γ spectrometer and 26.2% for LaBr γ spectrometer, respectively. The MDA was 12.26-14.74 Bq (measuring time: 3-5 min) for HPGe γ spectrometer and 56.56-80.37 Bq for LaBr γ spectrometer (measuring time: 2-4 min). The annual committed effective dose corresponding to MDA was 0.07-0.08 mSv (3-5 min) for HPGe and 0.31-0.45 mSv (2-4 min) for LaBr, respectively, in the case of using chronic continuous intake mode and 7 d monitoring period. Conclusions:The minimum detectable activity (MDA) of the two types of portable spectrometers could meet the requirements specified in GBZ 129-2016 Specifications for individual monitoring of occupational internal exposure for thyroid monitoring equipment. The two types of spectrometers could be used for routine monitoring of internal contamination. The difference between the monitoring result of LaBr γ and HPGe γ spectrometers might be due to such factors as large uncertainty in short measuring time and low activity concentrations, incomplete identical of distance between probe and neck, probe angle setting, different response of equipment to the environment, background deduction method.

Animals ; Antlers ; Exosomes ; Mesenchymal Stem Cells ; Osteoarthritis/therapy*

Objective:To ascertain the activity concentration of gross α and β in foods around Fuqing nuclear power plant (NPP) site.Methods:Totally 167 food samples of 25 kinds within 6 categories were collected from the surveillance areas and control areas around Fuqing NPP site. The total radioactivity was analyzed using the food samples. Paired rank sum test was used to determine the influence of the operation of Fuqing NPP on the total radioactivity in foods in surrounding areas. The multiple local rank sum test was used to assess the difference in total radioactivity in different types of foods.Results:The average gross α in poultry meat, vegetables, crops, aquatic products, milk and tea was 0.65, 1.96, 1.41, 3.80, 1.33, 7.67 Bq/kg in surveillance areas and 0.56, 3.24, 2.04, 3.70, 2.24, 9.05 Bq/kg in reference areas, respectively, around Fuqing NPP site. The average gross β (subtracting 40K) in poultry meat, vegetables, crops, aquatic products, milk and tea was 7.0, 10.5, 6.1, 23.5, 24.7, 8.6 Bq/kg in surveillance areas and 7.4, 8.3, 14.5, 22.1, 21.3, 11.0 Bq/kg in reference areas, respectively, around Fuqing NPP site. The Wilcoxon paired rank test showed that there was no significant difference in the gross α and β in foods between surveillance and reference areas around Fuqing NPP site ( P>0.05). The Kruskal-Wallis H test showed that the radioactivity of gross α and β in different foods was statistically significant ( χ2=23.325, 13.918, P<0.05). Conclusions:The increase was not found in total radioactivity in the surrounding foods since the operation of Fuqing NPP in 2015.

Exosomes are cell-derived nanovesicles with diameters from 30 to 150 nm, released upon fusion of multivesicular bodies with the cell surface. They can transport nucleic acids, proteins, and lipids for intercellular communication and activate signaling pathways in target cells. In cancers, exosomes may participate in growth and metastasis of tumors by regulating the immune response, blocking the epithelial-mesenchymal transition, and promoting angiogenesis. They are also involved in the development of resistance to chemotherapeutic drugs. Exosomes in liquid biopsies can be used as non-invasive biomarkers for early detection and diagnosis of cancers. Because of their amphipathic structure, exosomes are natural drug delivery vehicles for cancer therapy.

Objective:To explore the assessment methodology for internal dose to workers exposed to 131I radionuclide. Methods:Workers were chosen in a 131I radiopharmaceutial manufacturer and a nuclear medicine department in a hospital using 131I to treat hyperthyroidism and thyroid cancer. A portable high purity germanium (HPGe) gamma spectrometer was used to measure the content of 131I in the thyroid for 4 consecutive times in a period of 7 d. The internal dose was estimated combining with the work rotation mode for workers dealing with 131I. Results:When the monitoring month was used as a typical month to estimate the internal dose, the annual committed effective dose was 0.09-1.93 mSv for the production staff engaged in the repackaging of 131I radiopharmaceuticals in the surveyed enterprise, and 0.06-0.58 mSv for the nuclear medicine staff in the surveyed hospital. After adjusting the monitoring result of the current monitoring period based on the rotation mode, the annual committed effective dose was estimated to be 0.06-1.22 mSv for radiopharmaceutical production workers and 0.03-0.15 mSv for nuclear medicine workers, respectively. Conclusions:In the assessment of internal dose to radiation workers exposed to 131I, using a single time measurement result to estimate the annual dose would lead to a larger error. In the case of continuous monitoring, the result of subsequent monitoring periods should be corrected according to the result of previous monitoring periods. In order to accurately estimate the internal dose of workers exposed to 131I, it is necessary to take full account of the 131I exposure pattern, time and frequency and the internal contamination route. For workers who may be exposed to 131I with potential internal dose greater than 1 mSv/year, a 14 day-routine monitoring period was appropriate.