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The spatiotemporal heterogeneity of neurons, circuits and regulators is being uncovered at a single‐cell level, from single‐cell gene expression to functional regulations. The classifications, architectonics and functional communications amongst neural cells and circuits within the brain can be clearly delineated using single‐cell multiomics and transomics. This Editorial highlights the spatiotemporal heterogeneity of neurons and circuits as well as regulators, initiates the translation of neuronal diversity and spatial organisation at single‐cell levels into clinical considerations, and enables the discovery and development of new therapies for neurological diseases. It is predicted that single‐cell and spatial multiomics will be integrated with metabolomic profiles and corresponding gene epigenetic modifications. The interactions amongst DNAs, RNAs and proteins in a cell provide details of intracellular functional regulations and new opportunities for the translation of temporospatial diversity of neural cell subtypes/states into clinical practice. The application of single‐cell multiomics with four‐dimensional genome to the human pathological brain will lead us to a new milestone of the diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Metabolic abnormalities represent one of the pathological features of chronic obstructive pulmonary disease (COPD). Glutamic pyruvate transaminase 2 (GPT2) is involved in glutamate metabolism and lipid synthesis pathways, whilst the exact roles of GPT2 in the occurrence and development of COPD remains uncertain. This study aims at investigating how GPT2 and the associated genes modulate smoking‐induced airway epithelial metabolism and damage by reprogramming lipid synthesis. The circulating or human airway epithelial metabolomic and lipidomic profiles of COPD patients or cell‐lines explored with smoking were assessed to elucidate the pivotal roles of GPT2 in reprogramming processes. We found that GPT2 regulate the reprogramming of lipid metabolisms caused by smoking, especially phosphatidylcholine (PC) and triacylglycerol (TAG), along with changes in the expression of lipid metabolism‐associated genes. GPT2 modulated cell sensitivities and survival in response to smoking by enhancing mitochondrial functions and maintaining lipid and energy homeostasis. Our findings provide evidence for the involvement of GPT2 in the reprogramming of airway epithelial lipids following smoking, as well as the molecular mechanisms underlying GPT2‐mediated regulation, which may offer an alternative of therapeutic strategies for chronic lung diseases. [ABSTRACT FROM AUTHOR]

Peripheral immune cells play important roles in the maintenance of systemic and microenvironmental hemostasis. Measurements of circulating blood cells by single‐cell RNA sequencing (scRNA‐seq) were proposed as one of the routine measures in clinical biochemistry of hematology. Out of translational challenges, defining precise identities of cell subsets and states is more difficult, due to the complexity of immune cell development, location, regulation, function, and metabolism. It is also a challenge to precisely interpret clinical significance and impact of each cell identity marker gene panel (ciMGPs). ciMGPs have potential to advance the understanding of systemic responses of the disease, identify disease‐specific biomarkers, and to define cell heterogeneity. Recently, a large number of peripheral cell subsets and expending/activating states have been identified and validated for use in the fast developments in clinical single cell biomedicine. Defining specificity, measurability, and repeatability of cell subsets/states is important for translation of peripheral scRNA‐seq in clinical hematology and biochemistry. The development of standard operating procedure and performance of clinical trials in large populations at various ages, diseases, and therapies will promote the clinical translation of ciMGPs to measures. Thus, defining cell subset/state identities will provide the multi‐dimensional and comprehensive readouts of systemic immune cells, the precision monitoring of immune dynamics, and deeper‐understanding of the disease and response to therapy. [ABSTRACT FROM AUTHOR]

Background: Lung epithelial cells play important roles in lung inflammation and injury, although mechanisms remain unclear. Osteopontin (OPN) has essential roles in epithelial damage and repair and in lung cancer biological behaviours. Telocyte (TC) is a type of interstitial cell that interacts with epithelial cells to alleviate acute inflammation and lung injury. The present studies aim at exploring potential mechanisms by which OPN regulates the epithelial origin lung inflammation and the interaction of epithelial cells with TCs in acute and chronic lung injury. Methods: The lung disease specificity of OPN and epithelial inflammation were defined by bioinformatics. We evaluated the regulatory roles of OPN in OPN‐knockdown or over‐expressed bronchial epithelia (HBEs) challenged with cigarette smoke extracts (CSE) or in animals with genome OPN knockout (gKO) or lung conditional OPN knockout (cKO). Acute lung injury and chronic obstructive pulmonary disease (COPD) were induced by smoking or lipopolysaccharide (LPS). Effects of OPN on PI3K subunits and ERK were assessed using the inhibitors. Spatialization and distribution of OPN, OPN‐positive epithelial subtypes, and TCs were defined by spatial transcriptomics. The interaction between HBEs and TCs was assayed by the co‐culture system. Results: Levels of OPN expression increased in smokers, smokers with COPD, and smokers with COPD and lung cancer, as compared with healthy nonsmokers. LPS and/or CSE induced over‐production of cytokines from HBEs, dependent upon the dysfunction of OPN. The severity of lung inflammation and injury was significantly lower in OPN‐gKO or OPN‐cKO mice. HBEs transferred with OPN enhanced the expression of phosphoinositide 3‐kinase (PI3K)CA/p110α, PIK3CB/p110β, PIK3CD/p110δ, PIK3CG/p110γ, PIK3R1, PIK3R2 or PIK3R3. Spatial locations of OPN and OPN‐positive epithelial subtypes showed the tight contact of airway epithelia and TCs. Epithelial OPN regulated the epithelial communication with TCs, and the down‐regulation of OPN induced more alterations in transcriptomic profiles than the up‐regulation. Conclusion: Our data evidenced that OPN regulated lung epithelial inflammation, injury, and cell communication between epithelium and TCs in acute and chronic lung injury. The conditional control of lung epithelial OPN may be an alternative for preventing and treating epithelial‐origin lung inflammation and injury. [ABSTRACT FROM AUTHOR]

Lung cancer is a widespread malignancy with a high death rate and disorder of lipid metabolism. Lysophosphatidylcholine (lysoPC) has anti‐tumour effects, although the underlying mechanism is not entirely known. The purpose of this study aims at defining changes in lysoPC in lung cancer patients, the effects of lysoPC on lung cancer cells and molecular mechanisms. Lung cancer cell sensitivity to lysoPC was evaluated and decisive roles of long‐chain acyl‐coenzyme A synthase 5 (ACSL5) in lysoPC regulation were defined by comprehensively evaluating transcriptomic changes of ACSL5‐downregulated epithelia. ACSL5 over‐expressed in ciliated, club and Goblet cells in lung cancer patients, different from other lung diseases. LysoPC inhibited lung cancer cell proliferation, by inducing mitochondrial dysfunction, altering lipid metabolisms, increasing fatty acid oxidation and reprograming ACSL5/phosphoinositide 3‐kinase/extracellular signal‐regulated kinase‐regulated triacylglycerol‐lysoPC balance. Thus, this study provides a general new basis for the discovery of reprogramming metabolisms and metabolites as a new strategy of lung cancer precision medicine. [ABSTRACT FROM AUTHOR]

With rapid developments of single‐cell sequencing and multi/trans‐omics, clinical single‐cell biomedicine is a new and emergent discipline to integrate single‐cell molecular and clinical phenomes and uncover new disease‐specific diagnoses and therapy. The journal of Clinical and Translational Medicine (CTM) launches the first CTM initiative of clinical single‐cell biomedicine (cscBioMed) to promote the discovery and development of single‐cell‐based biology and medicine, speed the translation from single‐cell biology into clinical application, and improve early diagnosis and therapy for human diseases. The cscBioMed initiative is speeding translational processes from circulating single‐cell RNA sequencing into routine measures in clinical biochemistry of haematology, from spatial transcriptomics into single‐cell pathology, and from single‐cell‐based biomarkers and targets into clinical diagnostics and target drugs. With a clear goal, we expect that cscBioMed will benefit human health by establishing a clinical single‐cell dynamic monitoring and early predicting system and by improving diagnosis and treatment. [ABSTRACT FROM AUTHOR]

In conclusion, for the first time, we developed the criteria to evaluate the ciMGPs specificity of lung cell types/subtypes from various lung diseases and characterized three categories of cell-specific, cell-associated, and cell-reference ciMGPs on basis of scRNA-seq. Intricated cell types and subtypes are defined by the provided cell annotations and further validated using cell identity marker gene panels (ciMGPs),[6] so the specificity of ciMGPs is critical to construct the single-cell profile. Of those cells, immune cells resident in the lung tissue included nine subtypes of lymphoid cells and 15 subtypes of myeloid cells,[8] and lung parenchymal cells had 15 subtypes of epithelia, nine of endothelia and nine of stromal cells, as presented in Figures S1-S48 and details in Tables S6-S11. [Extracted from the article]

General control non-repressible 5-related I N i -acetyltransferases (GNAT) family members ( I n i = 24) are primarily involved in the histone acetylation and translation process, to promote gene expression. Transcriptomic atlas of GNAT family members in pulmonary epithelia under pathological conditions using single-cell and bulk cell sequencing In order to elucidate the potential mechanism of GNAT family genes in lung diseases, we summarized and exampled critical pathways of GNAT family genes-associated regulations in gene expression of potential targets responsible for the development of lung diseases (Figure S1). [Extracted from the article]

Background: Hypercholesterolemia is found in patients with chronic lung inflammation, during which airway epithelial cells play important roles in maintenance of inflammatory responses to pathogens. The present study aims at molecular mechanisms by which cholesterol changes airway epithelial sensitivity in response to smoking. Methods: Human bronchial epithelial cells (HBEs) were stimulated with cigarette smoke extract (CSE) and mice were exposed to CS/lipopolysaccharide (LPS) as models in vitro and in vivo. Severe COPD patients and healthy volunteers were also enrolled and the level of cholesterol in plasma was detected by metabolomics. Filipin III and elisa kits were used to stain free cholesterol. Mitochondrial function was detected by mitotracker green, mitotracker green, and Seahorse. Mitochondrial morphology was detected by high content screening and electron microscopy. The mRNA and protein levels of mitochondrial dynamics‐related proteins were detected by RT‐qPCR and Western blot,respectively. BODIPY 493/503 was used to stain lipid droplets. Lipidomics was used to detect intracellular lipid components. The mRNA level of interleukin (IL)‐6 and IL‐8 were detected by RT‐qPCR. Results: We found that the cholesterol overload was associated with chronic obstructive pulmonary disease (COPD) and airway epithelia‐driven inflammation, evidenced by hypercholesterolemia in patients with COPD and preclinical models, alteration of lipid metabolism‐associated genes in CSE‐induced airway epithelia and production of ILs. External cholesterol altered airway epithelial sensitivity of inflammation in response to CSE, through the regulation of STARD3‐MFN2 pathway, cholesterol re‐distribution, altered transport and accumulation of cholesterol, activities of lipid transport regulators and disorder of mitochondrial function and dynamics. MFN2 down‐regulation increased airway epithelial sensitivity and production of ILs after smoking, at least partially by injuring fatty acid oxidation and activating mTOR phosphorylation. Conclusions: Our data provide new insights for understanding molecular mechanisms of cholesterol‐altered airway epithelial inflammation and for developing diagnostic biomarkers and therapeutic targets to improve patient outcomes. [ABSTRACT FROM AUTHOR]

Single‐cell RNA sequencing (scRNA‐seq) is considered an important approach to understand the molecular mechanisms of cancer microenvironmental functions and has the potential for clinical and translational discovery and development. The recent concerns on the impact of scRNA‐seq for clinical practice are whether scRNA can be applied as a routine measurement of clinical biochemistry to assist in clinical decision‐making for diagnosis and therapy. Pushing single‐cell sequencing into clinical application is one of the important missions for clinical and translational medicine (CTM), although there still are a large number of challenges to be overcome. The present Editorial as one of serials aims at overviewing the history of scRNA‐seq publications in CTM, sharing the understanding and consideration of the cancer microenvironment at the single‐cell solution and emphasising the objective of translating scRNA‐seq into clinical application. The dynamic characteristics and patterns of single‐cell identity, regulatory networks, and intercellular communication play decisive roles in the properties of the microenvironment, malignancy and migrative capacity of cancer cells, and defensive capacity of immune cells. The microenvironmental single‐cell transcriptomic profiles and cell clusters defined by scRNA‐seq have great value for exploring the molecular mechanisms of diseases and predicting cell sensitivities to therapy and patient prognosis. [ABSTRACT FROM AUTHOR]