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Cells May 2024The bone marrow (BM) stromal cell microenvironment contains non-hematopoietic stromal cells called mesenchymal stromal cells (MSCs). MSCs are plastic adherent, form... (Review)
Review
The bone marrow (BM) stromal cell microenvironment contains non-hematopoietic stromal cells called mesenchymal stromal cells (MSCs). MSCs are plastic adherent, form CFU-Fs, and give rise to osteogenic, adipogenic, chondrogenic progenitors, and most importantly provide HSC niche factor chemokine C-X-C motif ligand 12 (CXCL12) and stem cell factor (SCF). Different authors have defined different markers for mouse MSC identification like PDGFRSca-1 subsets, Nestin, or LepR cells. Of these, the LepR cells are the major source of SCF and CXCL12 in the BM microenvironment and play a major role in HSC maintenance and hematopoiesis. LepR cells give rise to most of the bones and BM adipocytes, further regulating the microenvironment. In adult BM, LepR cells are quiescent but after fracture or irradiation, they proliferate and differentiate into mesenchymal lineage osteogenic, adipogenic and/or chondrogenic cells. They also play a crucial role in the steady-state hematopoiesis process, as well as hematopoietic regeneration and the homing of hematopoietic stem cells (HSCs) after myeloablative injury and/or HSC transplantation. They line the sinusoidal cavities, maintain the trabeculae formation, and provide the space for HSC homing and retention. However, the LepR cell subset is heterogeneous; some subsets have higher adipogenic potential, while others express osteollineage-biased genes. Different transcription factors like Early B cell factor 3 (EBF3) or RunX2 help maintain this balance between the self-renewing and committed states, whether osteogenic or adipogenic. The study of LepR MSCs holds immense promise for advancing our understanding of HSC biology, tissue regeneration, metabolic disorders, and immune responses. In this review, we will discuss the origin of the BM resident LepR cells, different subtypes, and the role of LepR cells in maintaining hematopoiesis, osteogenesis, and BM adipogenesis following their multifaceted impact.
Topics: Mesenchymal Stem Cells; Animals; Humans; Receptors, Leptin; Bone Marrow Cells; Bone and Bones; Hematopoiesis; Bone Marrow; Cell Differentiation
PubMed: 38891042
DOI: 10.3390/cells13110910 -
Scientific Reports Jun 2024The sinus node (SN) serves as the primary pacemaker of the heart and is the first component of the cardiac conduction system. Due to its anatomical properties and sample...
The sinus node (SN) serves as the primary pacemaker of the heart and is the first component of the cardiac conduction system. Due to its anatomical properties and sample scarcity, the cellular composition of the human SN has been historically challenging to study. Here, we employed a novel deep learning deconvolution method, namely Bulk2space, to characterise the cellular heterogeneity of the human SN using existing single-cell datasets of non-human species. As a proof of principle, we used Bulk2Space to profile the cells of the bulk human right atrium using publicly available mouse scRNA-Seq data as a reference. 18 human cell populations were identified, with cardiac myocytes being the most abundant. Each identified cell population correlated to its published experimental counterpart. Subsequently, we applied the deconvolution to the bulk transcriptome of the human SN and identified 11 cell populations, including a population of pacemaker cardiomyocytes expressing pacemaking ion channels (HCN1, HCN4, CACNA1D) and transcription factors (SHOX2 and TBX3). The connective tissue of the SN was characterised by adipocyte and fibroblast populations, as well as key immune cells. Our work unravelled the unique single cell composition of the human SN by leveraging the power of a novel machine learning method.
Topics: Humans; Sinoatrial Node; Myocytes, Cardiac; Single-Cell Analysis; Mice; Animals; Artificial Intelligence; Transcriptome; Heart Atria; Deep Learning
PubMed: 38890395
DOI: 10.1038/s41598-024-63542-6 -
Scientific Reports Jun 2024Lipid metabolism is an important part of the heart's energy supply. The expression pattern and molecular mechanism of lipid metabolism-related genes (LMRGs) in acute...
Lipid metabolism is an important part of the heart's energy supply. The expression pattern and molecular mechanism of lipid metabolism-related genes (LMRGs) in acute myocardial infarction (AMI) are still unclear, and the link between lipid metabolism and immunity is far from being elucidated. In this study, 23 Common differentially expressed LMRGs were discovered in the AMI-related mRNA microarray datasets GSE61144 and GSE60993. These genes were mainly related to "leukotriene production involved in inflammatory response", "lipoxygenase pathway", "metabolic pathways", and "regulation of lipolysis in adipocytes" pathways. 12 LMRGs (ACSL1, ADCY4, ALOX5, ALOX5AP, CCL5, CEBPB, CEBPD, CREB5, GAB2, PISD, RARRES3, and ZNF467) were significantly differentially expressed in the validation dataset GSE62646 with their AUC > 0.7 except for ALOX5AP (AUC = 0.699). Immune infiltration analysis and Pearson correlation analysis explored the immune characteristics of AMI, as well as the relationship between these identified LMRGs and immune response. Lastly, the up-regulation of ACSL1, ALOX5AP, CEBPB, and GAB2 was confirmed in the mouse AMI model. Taken together, LMRGs ACSL1, ALOX5AP, CEBPB, and GAB2 are significantly upregulated in AMI patients' blood, peripheral blood of AMI mice, myocardial tissue of AMI mice, and therefore might be new potential biomarkers for AMI.
Topics: Myocardial Infarction; Lipid Metabolism; Humans; 5-Lipoxygenase-Activating Proteins; Gene Expression Profiling; Animals; Arachidonate 5-Lipoxygenase; Gene Expression Regulation; Mice; Male; Coenzyme A Ligases
PubMed: 38890389
DOI: 10.1038/s41598-024-65022-3 -
The Journal of Clinical Investigation Jun 2024Myostatin (MSTN) has long been recognized as a critical regulator of muscle mass. Recently, there has been an increasing interest in its role in metabolism. In our...
Myostatin (MSTN) has long been recognized as a critical regulator of muscle mass. Recently, there has been an increasing interest in its role in metabolism. In our study, we specifically knocked out MSTN in brown adipose tissue (BAT) from mice (MSTNΔUCP1) and found that the mice gained more weight than controls when fed a high-fat diet, with progressive hepatosteatosis and impaired skeletal muscle activity. RNA-seq analysis indicated signatures of mitochondrial dysfunction and inflammation in the MSTN-ablation BAT. Further studies demonstrated that the the Kruppel-like factor 4 (KLF4) was responsible for the metabolic phenotypes observed, while FGF21 contributed to the microenvironment communication between adipocytes and macrophages induced by the loss of MSTN. Moreover, the MSTN-SMAD2/3-p38 signaling pathway mediated the expression of KLF4 and FGF21 in adipocytes. In summary, our findings suggest that brown adipocytes-derived MSTN regulates BAT thermogenesis via autocrine and paracrine effects on adipocytes or macrophages, ultimately regulating systemic energy homeostasis.
PubMed: 38889010
DOI: 10.1172/JCI178303 -
Cancer Research Communications Jun 2024Obesity is a modifiable predisposition factor for postmenopausal breast cancer. This suggests a localized, reciprocal interaction between breast cancer cells and the...
Obesity is a modifiable predisposition factor for postmenopausal breast cancer. This suggests a localized, reciprocal interaction between breast cancer cells and the surrounding mammary white adipose tissue. To investigate how breast cancer cells alter the composition and function of adipose tissue, we screened the secretomes of ten human breast cancer cell lines for the ability to modulate the differentiation of adipocyte stem and progenitor cells. The screen identified an adipogenic modulator, Zinc Alpha-2-Glycoprotein (ZAG/AZGP1) that is secreted by triple-negative breast cancer (TNBC) cells. TNBC-secreted ZAG inhibits adipogenesis and instead induces the expression of fibrotic genes. Accordingly, depletion of ZAG in TNBC cells attenuates fibrosis in white adipose tissue and inhibits tumor growth. Further, high expression of ZAG is linked to poor prognosis in TNBC patients, but not in patients with other clinical subtypes of breast cancer. Our findings suggest a role of TNBC-secreted ZAG in promoting the transdifferentiation of adipocyte stem and progenitor cells into cancer-associated fibroblasts to support tumorigenesis.
PubMed: 38888911
DOI: 10.1158/2767-9764.CRC-24-0218 -
Frontiers in Endocrinology 2024Unlike white adipose tissue depots, bone marrow adipose tissue (BMAT) expands during caloric restriction (CR). Although mechanisms for BMAT expansion remain unclear,...
Deficiency of glucocorticoid receptor in bone marrow adipocytes has mild effects on bone and hematopoiesis but does not influence expansion of marrow adiposity with caloric restriction.
INTRODUCTION
Unlike white adipose tissue depots, bone marrow adipose tissue (BMAT) expands during caloric restriction (CR). Although mechanisms for BMAT expansion remain unclear, prior research suggested an intermediary role for increased circulating glucocorticoids.
METHODS
In this study, we utilized a recently described mouse model () to exclusively target bone marrow adipocytes (BMAds) for elimination of the glucocorticoid receptor (GR) (i.e. ) whilst maintaining GR expression in other adipose depots.
RESULTS
Mice lacking GR in BMAds ( ) and control mice ( ) were fed or placed on a 30% CR diet for six weeks. On a normal chow diet, tibiae of female mice had slightly elevated proximal trabecular metaphyseal bone volume fraction and thickness. Both control and mice had increased circulating glucocorticoids and elevated numbers of BMAds in the proximal tibia following CR. However, no significant differences in trabecular and cortical bone were observed, and quantification with osmium tetroxide and μCT revealed no difference in BMAT accumulation between control or mice. Differences in BMAd size were not observed between and control mice. Interestingly, mice had decreased circulating white blood cell counts 4 h into the light cycle.
DISCUSSION
In conclusion, our data suggest that eliminating GR from BMAd has minor effects on bone and hematopoiesis, and does not impair BMAT accumulation during CR.
Topics: Animals; Receptors, Glucocorticoid; Caloric Restriction; Mice; Adipocytes; Adiposity; Female; Hematopoiesis; Bone Marrow; Mice, Knockout; Bone and Bones; Mice, Inbred C57BL; Adipose Tissue; Male; Metabolism, Inborn Errors
PubMed: 38887268
DOI: 10.3389/fendo.2024.1397081 -
Biology Methods & Protocols 2024Mapping protein interaction complexes in their natural state is arguably the Holy Grail of protein network analysis. Detection of protein interaction stoichiometry has...
Mapping protein interaction complexes in their natural state is arguably the Holy Grail of protein network analysis. Detection of protein interaction stoichiometry has been an important technical challenge, as few studies have focused on this. This may, however, be solved by artificial intelligence (AI) and proteomics. Here, we describe the development of HaloTag-based affinity purification mass spectrometry (HaloMS), a high-throughput HaloMS assay for protein interaction discovery. The approach enables the rapid capture of newly expressed proteins, eliminating tedious conventional one-by-one assays. As a proof-of-principle, we used HaloMS to evaluate the protein complex interactions of 17 regulatory proteins in human adipocytes. The adipocyte interactome network was validated using an pull-down assay and AI-based prediction tools. Applying HaloMS to probe adipocyte differentiation facilitated the identification of previously unknown transcription factor (TF)-protein complexes, revealing proteome-wide human adipocyte TF networks and shedding light on how different pathways are integrated.
PubMed: 38884001
DOI: 10.1093/biomethods/bpae039 -
Translational Cancer Research May 2024Patients with distant metastases have an unfavourable prognosis, but patients with isolated pulmonary metastases should generally not be considered hopeless. Complete...
The impact of the location, incidence and distribution of lung metastases in primary colorectal and renal cell cancer patients on prognosis: a retrospective observational study.
BACKGROUND
Patients with distant metastases have an unfavourable prognosis, but patients with isolated pulmonary metastases should generally not be considered hopeless. Complete resection of metachronous and solitary metastases leads to prolonged survival; however, the influence of the location, distribution and bilaterality of pulmonary metastases needs to be investigated further. This article aimed to investigate the role of the distribution of lung metastases in primary colorectal and renal cell cancer patients on prognosis.
METHODS
We retrospectively investigated the prognosis of patients with pulmonary metastases and colorectal or renal cell carcinoma, defined as the survival time of patients with different metastases. The types of metastases were unilobar, multilobar, unilateral, bilateral, diffuse, synchronous, or metachronous. The secondary outcome of this study was differences in prognosis according to additional criteria.
RESULTS
Patients with metachronous metastases had significantly greater median survival than patients with synchronous metastases. There was a statistically significant difference in median survival between patients with unilateral (better survival) and patients with bilateral (worse survival) lung metastases. In patients with renal cell carcinoma, a statistically significant difference in median survival time was detected for patients with unilateral metastases. A significantly longer median survival time was observed in patients without diffuse metastases. A significantly greater median survival time was detected in patients with no thoracic nodal involvement. Moreover, there was no statistically significant difference in the median survival time for patients with colorectal versus renal cell carcinoma in general or for those with lung metastases. No statistically significant difference in median survival time was detected for patients according to single or multiple lung metastases, additional tumours or metastases during disease, the distance of residence from a specialized clinic in Coburg, sex, smoking or adipocytes, multimorbidity, immunosuppression or different cancer treatments.
CONCLUSIONS
For a minority of patients, pulmonary resection is a chance for prolonged survival. The perioperative mortality rate after metastasectomy is less than five percent. Patients with metachronous and unilateral lung metastases should be evaluated for surgery. Patients with diffuse metastases or lymph node involvement have a significantly shorter median survival time. Decision-making should be interdisciplinary.
PubMed: 38881932
DOI: 10.21037/tcr-23-1961 -
SAGE Open Medicine 2024Dolutegravir is an integrase inhibitor and is recommended by the World Health Organization as the preferred first-line and second-line human immunodeficiency virus... (Review)
Review
Dolutegravir is an integrase inhibitor and is recommended by the World Health Organization as the preferred first-line and second-line human immunodeficiency virus treatment in all populations. Excessive weight gain associated with dolutegravir-based regimens is an emerging issue; however, the long-term metabolic consequences of this effect have not been fully understood. Growing evidence shows that this leads to a higher incidence of hyperglycemia, hypertension, and metabolic syndrome, along with elevated cardiovascular risk. Dolutegravir-based regimens, also associated with greater adipocyte differentiation and greater expression of markers associated with lipid storage, continue to be a problem among patients living with human immunodeficiency virus. The mechanisms by which certain antiretroviral therapy agents differentially contribute to weight gain remain unknown. Some clinical investigators speculate that dolutegravir could interfere with central nervous system appetite regulation (melanocortin-4 receptor) and insulin signaling, or may have better penetration of adipose tissue where they could exert a direct impact on adipose tissue adipogenesis, fibrosis, and insulin resistance. This review summarizes our current understanding of weight gain and fat changes associated with dolutegravir and its possible secondary metabolic comorbidities.
PubMed: 38881592
DOI: 10.1177/20503121241260613 -
Signal Transduction and Targeted Therapy Jun 2024
Topics: Humans; Janus Kinase 1; Pneumonia; Hypersensitivity; Animals; Asthma
PubMed: 38880827
DOI: 10.1038/s41392-024-01843-y