Biology subjects

Chen, X.

Publications and source records attributed to Chen, X..

At least 991 records · Page 55Linked to original sources

bioRxiv2022

Nuclear m6A Reader YTHDC1 Promotes Muscle Stem Cell Activation/Proliferation by Regulating mRNA Splicing and Nuclear Export

Skeletal muscle stem cells (also known as satellite cells, SCs) are essential for muscle regeneration and the regenerative activities of SCs are intrinsically governed by gene regulatory mechanisms but the post-transcriptional regulation in SCs remains largely unknown. N(6)-methyladenosine (m6A) modification of RNAs is the most pervasive and highly conserved RNA modification in eukaryotic cells and exerts powerful impact on almost all aspects of mRNA processing which is mainly endowed by its binding with m6A reader proteins. Here in this study, we investigate the previously uncharacterized regulatory roles of YTHDC1, a m6A reader in SCs. Our results demonstrate YTHDC1 is an essential regulator of SC activation and proliferation upon acute injury induced muscle regeneration. The induction of YTHDC1 is indispensable for SC activation and proliferation thus inducible YTHDC1 depletion almost abolishes SC regenerative capacity. Mechanistically, transcriptome-wide profiling using LACE-seq in both SCs and C2C12 myoblasts identifies m6A mediated binding targets of YTHDC1. Next, splicing analysis defines splicing mRNA targets of m6A-YTHDC1. Furthermore, nuclear export analysis also leads to identification of potential mRNA export targets of m6A-YTHDC1 in SCs and C2C12 myoblasts and interestingly some mRNAs can be regulated at both splicing and export levels. Lastly, we map YTHDC1 interacting protein partners in myoblasts and unveil a myriad of factors governing mRNA splicing, nuclear export and transcription, among which hnRNPG appears to be a bona fide interacting partner of YTHDC1. Altogether, our findings uncover YTHDC1 as an essential factor controlling SC regenerative ability through multi-faceted gene regulatory mechanisms in myoblast cells.

molecular biology↗

bioRxiv2022

Isoform-specific Disruption of the TP73 Gene Reveals a Critical Role for TAp73gamma in Tumorigenesis via Leptin

TP73, a member of the p53 family, is expressed as TAp73 and {Delta}Np73 along with multiple C-terminal isoforms (-{eta}). {Delta}Np73 is primarily expressed in neuronal cells and necessary for neuronal development. Interestingly, while TAp73 is a tumor suppressor and predominantly expressed in normal cells, TAp73 is found to be frequently altered in human cancers, suggesting a role of TAp73 C-terminal isoforms in tumorigenesis. To test this, the TCGA SpliceSeq database was searched and showed that exon 11 (E11) exclusion occurs frequently in several human cancers. We also found that p73 to p73{gamma} isoform switch resulting from E11 skipping occurs frequently in human prostate cancers and dog lymphomas. To determine whether p73 to p73{gamma} isoform switch plays a role in tumorigenesis, CRISPR technology was used to generate multiple cancer cell lines and a mouse model in that Trp73 E11 is deleted. Surprisingly, we found that in E11-deificient cells, p73{gamma} becomes the predominant isoform and exerts oncogenic activities by promoting cell proliferation and migration. In line with this, E11-deficient mice were more prone to obesity and B-cell lymphomas, indicating a unique role of p73{gamma} in lipid metabolism and tumorigenesis. Additionally, we found that E11-deficient mice phenocopies Trp73-deficient mice with short lifespan, infertility, and chronic inflammation. Mechanistically, Mechanistically, we showed that Leptin, a pleiotropic adipocytokine involved in energy metabolism and oncogenesis, was highly induced by p73{gamma}, necessary for p73{gamma}-mediated oncogenic activity, and associated with p73 to {gamma} isoform switch in human prostate cancer and dog lymphoma. Finally, we showed that E11-knockout promoted, whereas knockdown of p73{gamma} or Leptin suppressed, xenograft growth in mice. Our study indicates that the p73{gamma}-Leptin pathway promotes tumorigenesis and alters lipid metabolism, which may be targeted for cancer management.

cancer biology↗

bioRxiv2022

A histone deacetylase complex establishes a transgenerationally inherited maternal epigenetic state controlling progeny seed dormancy

Mother plants play an important role in the control of dormancy and dispersal characters of their progeny. In Arabidopsis seed dormancy is imposed by the embryo-surrounding tissues of the endosperm and seed coat. Here we show that the VERNALIZATION5/VIN3-LIKE 3 (VEL3) gene maintains maternal control over progeny seed dormancy by establishing an epigenetic state early in endosperm development that primes the depth of primary seed dormancy later established during seed maturation. VEL3 relocates MSI1 to the nucleolus and associates with other components of the histone deacetylase complex (HDAC), and is required for gene repression via PRC2 and HDAC at pericentromeric regions established in the central cell. Interestingly, the epigenetic state established by the maternal VEL3 is retained trans-generationally in mature seeds, and controls seed dormancy through the repression of programmed cell death-associated gene ORE1. Our data demonstrates a novel mechanism by which maternal control of progeny seed physiology persists post-shedding, maintaining parental control of seed behaviour.

developmental biology↗

bioRxiv2022

Pantothenate Kinase 4 Governs Lens Epithelial Fibrosis by Negatively Regulating PKM2 Related Glycolysis

Lens fibrosis is one of the leading causes of cataract in the elderly population. The primary energy substrate of the lens is glucose from the aqueous humor, and the transparency of mature lens epithelial cells (LECs) is dependent on glycolysis for ATP. Therefore, the deconstruction of reprogramming of glycolytic metabolism can contribute to further understanding of LEC epithelial-mesenchymal transition (EMT). In the present study, we found a novel pantothenate kinase 4 (PANK4)-related glycolytic mechanism that regulates LEC EMT. The PANK4 level was correlated with aging in cataract patients and mice. Loss of function of PANK4 significantly contributed to alleviating LEC EMT by upregulating pyruvate kinase M2 isozyme (PKM2), which was phosphorylated at Y105, thus switching oxidative phosphorylation to glycolysis. However, PKM2 regulation did not affect PANK4, demonstrating the downstream role of PKM2. Inhibition of PKM2 in Pank4-/- mice caused lens fibrosis, which supports the finding that the PANK4-PKM2 axis is required for LEC EMT. Glycolytic metabolism-governed hypoxia inducible factor (HIF) signaling is involved in PANK4-PKM2-related downstream signaling. However, HIF-1 elevation was independent of PKM2 (S37) but PKM2 (Y105) when PANK4 was deleted, which demonstrated that PKM2 and HIF-1 were not involved in a classic positive feedback loop. Collectively, these results indicate a PANK4-related glycolysis switch that may contribute to HIF-1 stabilization and PKM2 phosphorylation at Y105 and inhibit LEC EMT. The mechanism elucidation in our study may also shed light on fibrosis treatments for other organs.

cell biology↗

bioRxiv2022

Spatial mapping of human lung tissue reveals granuloma diversity and histopathological superstructure in tuberculosis

The histopathological hallmark of tuberculosis (TB) is the formation of immune cell enriched aggregates called granulomas, but the scope of granuloma heterogeneity in human TB is unknown. By spatially mapping individual immune cells across large regions of TB lung tissue, we report that in addition to necrotizing granulomas, the human TB lung contains abundant non-necrotizing leukocyte aggregates surrounding areas of necrotizing tissue. These cellular lesions were more diverse in composition than necrotizing lesions and could be stratified into four general classes based on cellular composition and spatial distribution of B cells and macrophages, indicating there are foci of distinct immune reactions adjacent to necrotizing granulomas. We further show that the specific cellular composition of non-necrotizing structures correlates with their proximity to necrotizing lesions. Together, our study shows that during tuberculosis diseased lung tissue develops a histopathological superstructure comprising at least four different types of non-necrotizing cellular aggregates organized as satellites of necrotizing granulomas.

immunology↗

bioRxiv2022

Expansion Sequencing of RNA Barcoded Neurons in the Mammalian Brain: Progress and Implications for Molecularly Annotated Connectomics

Mapping and molecularly annotating mammalian neural circuits is challenging due to the inability to uniquely label cells while also resolving subcellular features such as synaptic proteins or fine cellular processes. We argue that an ideal technology for connectomics would have the following characteristics: the capacity for robust distance-independent labeling, synaptic resolution, molecular interrogation, and scalable computational methods. The recent development of high-diversity cellular barcoding with RNA has provided a way to overcome the labeling limitations associated with spectral dyes, however performing all-optical circuit mapping has not been demonstrated because no method exists to image barcodes throughout cells at synaptic-resolution. Here we show ExBarSeq, an integrated method combining in situ sequencing of RNA barcodes, immunostaining, and Expansion Microscopy coupled with an end-to-end software pipeline that automatically extracts barcode identities from large imaging datasets without data processing bottlenecks. As a proof of concept, we applied ExBarSeq to thick tissue sections from mice virally infected with MAPseq viral vectors and demonstrated the extraction of 50 barcoded cells in the visual cortex as well as cell morphologies uncovered via immunostaining. The current work demonstrates high resolution multiplexing of exogenous barcodes and endogenous synaptic proteins and outlines a roadmap for molecularly annotated connectomics at a brain-wide scale.

neuroscience↗

bioRxiv2022

Pathogen effector-associated nuclear-localization of RPW8.2 amplifies its expression to boost immunity in Arabidopsis

RESISTANCE TO POWDERY MILDEW 8 (RPW8) defines a unique N-terminal coiled-coil domain of nucleotide-binding and leucine-rich repeat immune receptors required for immune signaling in plants. Arabidopsis RPW8.2 is specifically induced by the powdery mildew (PM) fungus (Golovinomyces cichoracearum) in the infected epidermal cells to activate immunity. The mechanism of RPW8.2-induction is not well understood. Here, we identify a G. cichoracearum factor delivered to the nucleus of the host cell, named Gc-RPW8.2 interacting protein 1 (GcR8IP1). Ectopic expression of GcR8IP1 in Arabidopsis or Nicotiana benthamiana suppressed host immune responses and enhanced susceptibility to PM. Host-induced gene silencing of GcR8IP1 compromised PM infectivity in susceptible Arabidopsis plants. Co-expression of GcR8IP1 with RPW8.2 increased nuclear localization of RPW8.2, which in turn, promoted transcriptional amplification of RPW8.2. Thus, RPW8.2-dependent defense strengthening is due to altered partitioning of RPW8.2 by an effector of a PM fungus, which exemplifies an atypical form of effector-triggered immunity.

plant biology↗

bioRxiv2022

ID1 functions as an autonomous phosphate (Pi) regulator upstream of the miR399-ZmPHO2 signaling module in maize

The macronutrient phosphorus is essential for plant growth and development. Plants have evolved multiple strategies to increase the efficiency of Pi acquisition to protect themselves from Pi starvation. However, the crosstalk between Pi homeostasis and plant development remains to be explored. Here, we report that overexpressing microRNA399 in maize induced a premature aging syndrome after pollination. Knockout of ZmPHO2, one of the miR399 targets, resulted in a similar premature aging phenotype. Strikingly, we found that INDETERMINATE1 (ID1), a floral transition regulator, inhibits the transcription of ZmMIR399 genes by directly binding to their promoters, alleviating the repression of ZmPHO2 by miR399 and ultimately contributing to the maintenance of Pi homeostasis in maize. Unlike ZmMIR399 genes, whose expression is induced by Pi deficiency, ID1 expression is independent of the Pi status, indicating that ID1 is an autonomous regulator of Pi homeostasis. Furthermore, we found that ZmPHO2 was under selection during maize domestication, resulting in a more sensitive response to phosphate starvation in temperate maize than in tropical maize. Our study reveals a direct functional link between Pi-deprivation sensing by the miR399-ZmPHO2 regulatory module and plant developmental regulation by ID1.

plant biology↗

bioRxiv2022

Chromatin accessibility profiling in tissue sections by spatial ATAC

Current methods for epigenomic profiling are limited in the ability to obtain genome wide information with spatial resolution. Here we introduce spatial ATAC, a method that integrates transposase-accessible chromatin profiling in tissue sections with barcoded solid-phase capture to perform spatially resolved epigenomics. We show that spatial ATAC enables the discovery of the regulatory programs underlying spatial gene expression during mouse organogenesis, lineage differentiation and in human pathological samples.

genomics↗

bioRxiv2022

Honey Bees Get Map Coordinates from the Dance

Honeybees (Apis mellifera carnica) communicate the rhumb line to a food source (its direction and distance from the hive) by means of a waggle dance. We ask whether bees recruited by the dance use it only as a flying instruction or also translate it into a location vector in a map-like memory, so that information about spatial relations of environmental cues informs their attempts to find the source. The flights of recruits captured on exiting the hive and released at distant sites were tracked by radar. The recruits performed first a straight flight in the direction of the rhumb line. However, the vector portions of their flights and the ensuing tortuous search portions were strongly and differentially affected by the release site. Searches were biased toward the true location of the food and away from the location specified by translating the rhumb line origin to the release site. We conclude that by following the dance a recruit gets two messages, a polar flying instruction (the rhumb line) and its conversion to Cartesian map coordinates.

animal behavior and cognition↗

bioRxiv2022

Engineering human Mucosal Associated Invariant T (MAIT) cells with chimeric antigen receptors for cancer immunotherapy

Engineering immune cells with chimeric antigen receptors (CAR) is a promising technology in cancer immunotherapy. Besides classical cytotoxic CD8+ T cells, innate cell types such as NK cells have also been used to generate CAR-T or CAR-NK cells. Here we devised an approach to program a non-classical cytotoxic T cell subset called Mucosal Associated Invariant T (MAIT) cells into effective CAR-T cells against B cell lymphoma and breast cancer cells. Accordingly, we expressed anti-CD19 and anti-Her2 CARs in activated primary human MAIT cells and CD8+ T cells, expanded them in vitro and compared their cytotoxicity against tumor cell targets. We show upon activation through CARs, CAR-MAIT cells exhibit high levels of cytotoxicity towards target cells, comparable to CD8+ CAR-T cells, but interestingly expressed lower levels of IFN-{gamma} than conventional CAR CD8+ T cells. Additionally, in the presence of vitamin B2 metabolite 5-ARU, which is a conserved compound that activates MAIT cells through MHC-I related (MR1) protein, MAIT cells killed MR1-expressing target breast cancer and B cell lymphoma cell lines in a dose dependent manner. Thus, MAIT cells can be genetically edited as CAR-T cells or mobilized and expanded by MR1 ligands as an off-the-shelf novel approach to cell-based cancer immunotherapy strategies while being comparable to conventional methods in effectivity. Key PointsO_LIMAIT cells expressing CARs effectively kill CD19 and Her2 expressing targets C_LIO_LICAR-MAITs display strong cytotoxicity with lower TNF-{gamma} compared to CD8+ CAR-T cells C_LI

immunology↗

bioRxiv2022

The response mechanism of oreorchis patens (Lindl.) Lindl. to cold stress

Cold stress, a major environmental factor, has an important impact on the production of landscape plants and crop yield, and its stress and resistance mechanisms have always been hot research issues. Oreorchis patens (Lindl.) Lindl., an important germplasm resource, has strong frost resistance and can resist low temperatures of -40 {degrees}C. However, the mechanism by which O. patens responds to cold stress remains poorly understood. Here, we examined the adaptation to the low-temperature environment of O. patens by changing the leaf tissue structure, while the synergistic effect of osmotic regulation, reactive oxygen scavenging and protein improved the resistance to cold stress. In addition, analysis of the photosynthetic system showed that cold stress changes the photosynthetic capacity of O. patens leaves to affect cold resistance. Analysis by nonparametric transcriptome sequencing revealed 2402 genes that were differentially expressed, most of which were related to resistance. Simultaneously, quantitative real-time polymerase chain reaction (qRT-PCR) analysis obtained results consistent with the transcriptome. These results indicated that O. patens could alter leaf structure and physiological and biochemical metabolic processes by initiating resistance-related molecular regulatory networks to improve the ability to resist cold stress. This study was the first to discuss the physiological, biochemical and molecular regulatory mechanisms of O. patens resistance to cold stress, which laid a foundation for revealing the biological and molecular mechanisms of overwintering of O. patens and breeding cold-resistant horticultural crops in northern China.

plant biology↗

bioRxiv2022

Drug degradation caused by mce3R mutations confers contezolid (MRX-I) resistance in Mycobacterium tuberculosis

Contezolid (MRX-I), a safer antibiotic of the linezolid oxazolidinone class, is a promising new antibiotic with potent activity against Mycobacterium tuberculosis (MTB) both in vitro and in vivo. To identify resistance mechanisms of contezolid in MTB, we isolated several in vitro spontaneous contezolid-resistant MTB mutants, which exhibited 16-fold increase in MICs of contezolid compared with the parent strain but was still unexpectedly susceptible to linezolid. Whole-genome sequencing revealed that most of the contezolid-resistant mutants bore mutations in the mce3R gene which encode a transcriptional repressor. The mutations in mce3R led to markedly increased expression of a monooxygenase encoding gene Rv1936. We then characterized Rv1936 as a putative flavin-dependent monooxygenase that catalyzes the degradation of contezolid into its inactive DHPO ring-opened metabolites, thereby conferring drug resistance. While contezolid is an attractive drug candidate with potent antimycobacterial activity and low toxicity, the occurrence of mutations in Mce3R should be considered when designing combination therapy using contezolid for treating tuberculosis. IMPORTANCETuberculosis (TB) is one of the leading causes of global death and the second deadliest infectious killer after COVID-19. Compared to drug-sensitive TB, the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB is more difficult and less effective due to longer regimens and higher potential for clinical adverse events. Despite the undisputed medical success of linezolid on MDR/XDR-TB therapy, this drug suffers from severe safety limitation. The new NMPA-approved drug contezolid, as an analogue of linezolid, exhibits a superior safety profile and potent antitubercular activity. Since the less-toxic contezolid is a promising drug candidate to optimize the current longer-duration MDR/XDR-TB therapy, it would be of significance to determine the resistance profiles of contezolid in MTB. Here, we present the first exploration of the frequency, mutational targets and molecular mechanisms of contezolid resistance in MTB, which could provide theoretical guidance for its future clinical application.

microbiology↗

bioRxiv2022

Multi-Molecular Hyperspectral PRM-SRS Imaging

Lipids play crucial roles in many biological processes under physiological and pathological conditions. Mapping spatial distribution and examining metabolic dynamics of different lipids in cells and tissues in situ are critical for understanding aging and diseases. Commonly used imaging methods, including mass spectrometry-based technologies or labeled imaging techniques, tend to disrupt the native environment of cells/tissues and have limited spatial or spectral resolution, while traditional optical imaging techniques still lack the capacity to distinguish chemical differences between lipid subtypes. To overcome these limitations, we developed a new hyperspectral imaging platform that integrates a Penalized Reference Matching algorithm with Stimulated Raman Scattering (PRM-SRS) microscopy. With this new approach, we directly visualized and identified multiple lipid species in cells and tissues in situ with high chemical specificity and subcellular resolution. High density lipoprotein (HDL) particles containing non-esterified cholesterol was observed in the kidney, indicating that these pools of cholesterol are ectopic deposits, or have yet to be enriched. We detected a higher Cholesterol to phosphatidylethanolamine (PE) ratio inside the granule cells of hippocampal samples in old mice, suggesting altered membrane lipid synthesis and metabolism in aging brains. PRM-SRS imaging also revealed subcellular distributions of sphingosine and cardiolipin in the human brain sample. Compared with other techniques, PRM-SRS demonstrates unique advantages, including faster data processing and direct user-defined visualization with enhanced chemical specificity for distinguishing clinically relevant lipid subtypes in different organs and species. Our method has broad applications in multiplexed cell and tissue imaging.

bioengineering↗

bioRxiv2022

In vivo functional genomics identifies essentiality of potassium homeostasis in medulloblastoma

The identification of cancer maintenance genes--driver genes essential to tumor survival--is fundamental for developing effective cancer therapy. Transposon-based insertional mutagenesis screens can identify cancer driver genes broadly but not discriminate maintenance from progression or initiation drivers, which contribute to cancer phenotypes and tumorigenesis, respectively. We engineered a nested, double-jumping transposon system to first dysregulate gene expression during tumorigenesis and then restore gene expression following tumor induction, allowing for genome-wide screening of maintenance essentiality in vivo. In a mouse model of medulloblastoma, the most common pediatric malignancy, insertion and remobilization of this nested transposon uncovers potassium channel genes as recurrent maintenance drivers. In human medulloblastoma, KCNB2 is the most overexpressed potassium channel across Group 3, Group 4, and SHH subgroups, and Kcnb2 knockout in mice diminishes the replicative potential of medulloblastoma-propagating cells to mitigate tumor growth. Kcnb2 governs potassium homeostasis to regulate plasma membrane tension-gated EGFR signaling, which drives proliferative expansion of medulloblastoma-propagating cells. Thus, our novel transposon system reveals potassium homeostasis as essential to tumor maintenance through biomechanical modulation of membrane signaling.

cancer biology↗

bioRxiv2022

Old Age Drives Fusion and Expansion of Vitellogenin Vesicles in the Intestine of Caenorhabditis elegans

Some of the most conspicuous aging phenotypes of C. elegans are related to post-reproductive production of vitellogenins (Vtg), which form yolk protein (YP) complexes after processing and lipid loading. Vtg/YP levels show huge increases with age, and inhibition of this extends lifespan, but how subcellular and organism-wide distribution of these proteins changes with age has not been systematically explored. Here this has been done to understand how vitellogenesis promotes aging. The age-associated changes of intestinal vitellogenin vesicles (VVs), pseudocoelomic yolk patches (PYPs), and gonadal yolk organelles (YOs) have been characterized by immuno-electron microscopy. We find that from reproductive adult day 2 (AD 2) to post-reproductive AD 6 and AD 9, intestinal VVs expand from 0.2 m to 3-4 m in diameter or by > 3,000 times in volume, PYPs increase by > 3 times in YP concentration and volume, while YOs in oocytes shrink slightly from 0.5 m to 0.4 m in diameter or by 60% in volume. In AD 6 and AD 9 worms, mis-localized YOs found in the hypodermis, uterine cells, and the somatic gonadal sheath can reach a size of 10 m across in the former two tissues. This remarkable size increase of VVs and that of mis-localized YOs in post-reproductive worms are accompanied by extensive fusion between these Vtg/YP-containing vesicular structures in somatic cells. In contrast, no fusion is seen between YOs in oocytes. We propose that in addition to the continued production of Vtg, excessive fusion between VVs and mislocalized YOs in the soma worsen the aging pathologies seen in C. elegans. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/501051v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@cfda97org.highwire.dtl.DTLVardef@180369org.highwire.dtl.DTLVardef@87eedaorg.highwire.dtl.DTLVardef@525384_HPS_FORMAT_FIGEXP M_FIG Graphical Summary: Age-dependent changes of vitellogenins-/yolk proteins-containing subcellular structures in C. elegans On the left is a young wild-type C. elegans of adult day 1 or 2, and on the right is an older worm of adult day 6 or 9. The orange-colored structures are: in the intestine, vitellogenin vesicles (VVs), of a median diameter of 200 nm on the left and 3-4 micrometers on the right, with a frequent fusion between VVs in the older worm; in the pseudocoelom, pseudocoelomic yolk patches, greatly expanded in the older worm; in oocytes and eggs, yolk organelles (YOs), of a median diameter of 500 nm on the left and 400 nm on the right; in the hypodermis, sheath or uterine cells of the older worm, mislocalized YOs. C_FIG

cell biology↗

bioRxiv2022

No evidence of theory of mind reasoning in the human language network

Language comprehension and the ability to infer others thoughts (theory of mind, ToM) are interrelated during development and language use. However, neural evidence that bears on the relationship between language and ToM mechanisms is mixed. Although robust dissociations have been reported in brain disorders, brain activations for contrasts that target language and ToM bear similarities, and some have reported overlap (Deen et al., 2015). We take another look at the language-ToM relationship by evaluating the response of the language network (Fedorenko et al., 2010), as measured with fMRI, to verbal and non-verbal ToM across 151 participants. Individual-subject analyses reveal that all core language regions respond more strongly when participants read vignettes about false beliefs compared to the control vignettes. However, we show that these differences are largely due to linguistic confounds, and no such effects appear in a non-verbal ToM task. These results argue against cognitive and neural overlap between language processing and ToM. In exploratory analyses, we find responses to social processing in the "periphery" of the language network--right hemisphere homotopes of core language areas and areas in bilateral angular gyri--but these responses are not selectively ToM-related and may reflect general visual semantic processing.

neuroscience↗

bioRxiv2022

Osteocytes regulate organismal senescence of bone and bone marrow

The skeletal system contains a series of sophisticated cellular lineages arisen from the mesenchymal stem cells (MSC) and hematopoietic stem cells (HSC), that determine the homeostasis of bone and bone marrow. Here we reasoned that osteocyte may exert a function in regulation of these lineage cell specifications and tissue homeostasis. Using a mouse model of conditional deletion of osteocytes by the expression of diphtheria toxin subunit (DTA) in dentin matrix protein 1 (DMP-1) positive osteocytes, we demonstrated that partial ablation of DMP-1positive osteocytes caused severe sarcopenia, osteoporosis and degenerative kyphosis, leading to shorter lifespan in these animals. Osteocyte reduction altered mesenchymal lineage commitment resulting in impairment of osteogenesis and induction of osteoclastogensis. Single cell RNA sequencing further revealed that hematopoietic lineage was mobilized towards myeloid lineage differentiation with expanded myeloid progenitors, neutrophils and monocytes, while the lymphopoiesis was impaired with reduced B cells in the osteocyte ablation mice. The acquisition of a senescence-associated secretory phenotype (SASP) in both osteoprogenic and myeloid lineage cells was the underlying cause. Together, we showed that osteocytes play critical roles in regulating of lineage cell specifications in bone and bone marrow through mediation of organismal senescence.

cell biology↗