Stromal Research Articles

Single cell analysis identified a basal cell transition state associated with the development and progression of bladder cancer

BackgroundBladder cancer (BC) is a prevalent malignancy characterized by significant cellular heterogeneity. While single-cell multi-omics studies have provided valuable insights, much of the existing data remains underexplored, limiting our understanding of BC’s molecular mechanisms. Uncovering the pathogenesis of BC and finding new treatment methods are urgent problems to be solved. This study aims to address this gap by re-analyzing available single-cell datasets to uncover novel insights into BC.MethodsIn this study, we retrieved three single-cell transcriptome datasets by searching the Gene Expression Omnibus (GEO) database, focusing on single-cell sequencing of normal mouse bladder within the past 5 years. Through quality control and batch effect elimination, we obtained a total of 24,930 cells including epithelial, stromal, and immune cells. Subgroup analysis, pseudotemporal analysis, cell–cell communication, and transcription factor analysis were conducted specifically on epithelial cells to identify a transitional state during basal cell differentiation. We further compared the expression profiles of key transcription factors in cancer and normal tissues. In addition, we also performed immunohistochemical staining and survival analysis for key transcription factors.ResultsSubgroup analysis revealed multiple subtypes of epithelial cells, including basal, umbrella, and intermediate cells. Through pseudotemporal analysis, we discovered the developmental trajectory from basal cells to umbrella cells and further found that Basal_I is a transitional state for basal cell differentiation. Cell-to-cell communication analyses highlighted the pivotal role of Basal_I in cell–cell interactions, and key ligand-receptor pairs associated with cancer progression were also identified. Furthermore, elevated expression levels of key transcription factors in Basal_I were found to be closely associated with the stage and prognosis of BC. Immunohistochemical staining results further confirmed the upregulated expression of these transcription factors in BC.ConclusionsCollectively, we found a transitional state of basal cells in normal bladder epithelial cells in mice, which may be related to the occurrence and development of BC, providing important clues for further understanding of the pathogenesis of BC. Our study provided possible molecular mechanisms or target for the research and treatment of BC.

Protective effect of bone-marrow stromal cells on injured cortical neurons subjected to hemostimulation in vitro

Objective: Bone-marrow mesenchymal stem cells (BMSCs) are a subpopulation of cells found in the bone marrow stromal of mammals that have the potential to differentiate and form bone, cartilage, adipose, neural, and muscle cells, with strong proliferative ability, multidirectional differentiation potential, immunomodulatory function. Here, we reported the novel findings on the effect of BMSC in protecting injured cortical neurons induced by hemostimulation. Methods: Cortical neurons harvested from the neonatal rat and were isolated and incubated at 37°C in a 5% CO2 environment. During this process, part of cells was subjected to hemostimulation, and BMSC derived supernatant addition was performed to observe its effect on neuroprotection. Hoechst 33342/PI co-staining and CCK-8 cell viability assays were utilized to evaluate the effects of BMSC supernatant administration on primary cortical neurons. Results: BMSC derived supernatant administration effectively protects hemoglobin-induced neuronal damage, indicating by cell viability-detection. In addition, BMSCs exert optimal effect by inhibiting neuronal cell apoptosis. Conclusions: BMSC derived supernatant treatment effectively ameliorates hemoglobin-induced neuronal damage and attenuates neuronal apoptosis.

Advancements in Cancer Research: 3D Models, Single‐Cell, and Live‐Cell Techniques for Better Insights

AbstractThe present review provides a comprehensive overview of the current state of in vitro cancer studies, focusing on recent advancements and ongoing in cell culture models and analyses techniques. Cancer cells grow in a complex and dynamic environment, interacting with various cellular components, such as stromal cells, cancer‐associated fibroblasts, immune cells, and the extracellular matrix (ECM). The ECM provides structural support and unique characteristics essential for tumorigenesis. Accurately modeling this intricate tumor microenvironment and precisely analyzing cell–cell and cell–ECM interactions are crucial for understanding cancer progression and therapeutic responses. Consequently, oncology research is advancing toward a) three‐dimensional tumor models, b) single‐cell level analyses, and c) live‐cell analyses. This review aims to elucidate current knowledge in this field, emphasizing the benefits these innovative approaches offer over traditional two‐dimensional models, bulk analyses, and endpoint measurements.

Utilizing follicular fluid on endometrial stromal cells enhances decidualization by induced inflammation

Utilizing follicular fluid on endometrial stromal cells enhances decidualization by induced inflammation

Intercellular junction-driven stromal cell stacking in a confined 3D microcavity

Understanding the detailed mechanisms driving fibroblast migration within native tissue settings during pathophysiological events presents a critical research challenge. In this study, we elucidate how stromal cells migrate and contribute to the development of three-dimensional (3D) cellular aggregates within confined microcavities. Integrin α5β1 and β-catenin (β-cat) are central in guiding this collective migration and achieving optimal filling of the microcavity. When β-cat is suppressed, cells tend to migrate more sporadically, leading to less efficient cellular organization. Furthermore, we also detail the pivotal roles of Cx43 and N-cadherin (N-cad) in orchestrating collective migration and in shaping efficient cellular stacking. Suppressing gap junctions, especially Cx43, significantly impacts the extracellular matrix expression, integrin α5 and β1, and other elements in the 3D construct, emphasizing the importance of physicochemical cell–cell interactions. The distribution patterns of N-cad and focal adhesion kinase (FAK) further corroborate the essential roles in forming cell–cell junctions and FAK in establishing the foundational layer that underpins the cell stacking within the microcavity. Interestingly, neither Rho-associated protein kinase (ROCK) nor RhoA significantly alter the cell migration pattern toward microcavity. These findings provide fresh perspectives on fibroblast activities in 3D space, enriching our understanding and offering implications for advancements in wound healing and tissue engineering.

Histopathological diagnosis of pulmonary sclerosing pneumocytoma in needle biopsy specimens

Objective: To investigate the diagnostic features of pulmonary sclerosing pneumocytoma (PSP) in needle biopsy specimens so as to improve the preoperative diagnostic accuracy and to prevent misdiagnoses. Methods: A total of 79 needle biopsy cases confirmed as PSP in surgical resection specimens were collected in the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China from January 2015 to January 2023. A retrospective analysis was conducted to investigate the clinical, pathological, and immunohistochemical characteristics of PSP. Results: Among the 79 cases, there were 8 males and 71 females, with an age range of 14 to 67 years (median 47 years). Among the 79 needle biopsy cases of PSP, 5 cases were initially misdiagnosed as adenocarcinoma and 1 as carcinoid preoperatively, while the remaining 73 cases were correctly diagnosed. 84.8% (67/79) of the PSP presented with well-defined, homogeneous, solitary solid tumors on chest imaging. Morphologically, 26.6% (21/79) of the PSP mainly showed a single histological component, 67.1% (53/79) contained two histological components, and 6.3% (5/79) contained three histological components. There were no cases containing all four histological components simultaneously. The tumor was composed of cuboidal cells on the surface and round cells in the stroma and lacked significant cytological atypia and mitotic figures. Some cases exhibited variations in histology and cellular morphology, such as glandular spaces (58.2%, 46/79), sclerotic papillae (46.8%, 37/79), hypercellularity (16.5%, 13/79), and cytological atypia (24.1%, 19/79). Immunophenotyping indicated that both tumor cell types expressed TTF1, EMA and β-catenin, while surface cells expressed pan-cytokeratin and Napsin A, and stromal cells expressed vimentin. In some cases, ER and PR were also expressed. Conclusions: When diagnosing PSP in needle biopsy specimens, the key to avoiding misdiagnosis is recognizing the presence of dual-cell populations within the tumor. The useful clues include presence of cellular papillae, mild cellular atypia, morphological diversity, interstitial foam-like cell aggregates, and prominent background hemorrhage and sclerosis. The characteristic immunophenotype and middle-aged female predilection are also helpful for the diagnosis of PSP.

From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression.

This review explores the progression of pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma through a dual lens of intrinsic molecular alterations and extrinsic microenvironmental influences. PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations driving PanIN initiation. Key additional mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and mothers against decapentaplegic homolog 4 (SMAD4) disrupt cell cycle control and genomic stability, crucial for PanIN progression from low-grade to high-grade dysplasia. Additional molecular alterations in neoplastic cells, including epigenetic modifications and chromosomal alterations, can further contribute to neoplastic progression. In parallel with these alterations in neoplastic cells, the microenvironment, including fibroblast activation, extracellular matrix remodeling, and immune modulation, plays a pivotal role in PanIN initiation and progression. Crosstalk between neoplastic and stromal cells influences nutrient support and immune evasion, contributing to tumor development, growth, and survival. This review underscores the intricate interplay between cell-intrinsic molecular drivers and cell-extrinsic microenvironmental factors, shaping PanIN predisposition, initiation, and progression. Future research aims to unravel these interactions to develop targeted therapeutic strategies and early detection techniques, aiming to alleviate the severe impact of pancreatic cancer by addressing both genetic predispositions and environmental influences.

Single-cell sequencing reveals cellular heterogeneity of nucleus pulposus in intervertebral disc degeneration

The nucleus pulposus (NP) plays a vital role in intervertebral disc degeneration (IVDD). Previous studies have revealed cellular heterogeneity in NP tissue during IVDD progression. However, the cellular and molecular alterations of diverse cell clusters during IVDD remain to be fully elucidated. NP tissues were isolated from patients with different grades of IVDD undergoing discectomy, and then subjected to single-cell RNA sequencing (scRNA-seq). Cell subsets were identified based on unbiased clustering of gene expression profiles. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to determine the molecular features of diverse cell clusters. Monocle analysis was used to illustrate the differentiation trajectories of chondrocytes. Additionally, CellPhoneDB analysis revealed potential interactions between chondrocytes and other cells during IVDD. Based on the expression profiles of 47,610 individual cells, eight putative clusters including chondrocytes, endothelial cells, fibroblasts, macrophages, mural cells, osteoclasts, proliferating stromal cells and T cells were identified. The chondrocyte cluster was classified into three subsets, C1-C3, which were associated with stress-resistance, fibrosis and inflammatory responses, respectively. Pseudo-time trajectories suggested that chondrocytes gradually differentiated into fibroblasts during IVDD. Immune cells including cDC2s, macrophages and monocytes were identified. Further analysis showed that chondrocytes might communicate with immune cells via the MIF, TNFSF9, SPP1 and CCL4L2 signaling pathways. In addition, we found that invading endothelial cells might interact with chondrocytes through the COL4A1, CXCL12, VEGFA and SEMA3E signaling pathways. Our results reveal the cellular complexity and phenotypic characteristics of NP tissues at single-cell resolution, which will contribute to the in-depth investigation of preventative and regenerative strategies for IVDD.

Intestinal stem cell niche: An upcoming area of immense importance in gastrointestinal disorders.

The intestinal stem cell (ISC) niche is vital for maintaining the integrity and function of the intestinal epithelium. ISC populations, characterized by their high proliferation and multipotency, reside within a specialized microenvironment at the base of crypts. Crypt base columnar (CBC) cells at the deepest part of crypts serve as replicating ISCs, while position 4 label-retaining cells (LRCs) located higher up in the crypts are also important for ISC maintenance during experiments. The interplay between CBCs, position 4 LRCs, transient amplifying (TA) cells and other niche components, including the pericrypt stromal cells, ensures a continuous supply of differentiated epithelial cells. Recent advancements in ISC biomarker studies have provided valuable insights into their molecular signatures, regulatory pathways and roles in the pathogenesis of intestinal disorders. Understanding the ISC niche has significant therapeutic implications, as manipulating ISC behaviors and regenerating damaged or diseased intestinal tissue show promise for novel therapeutic approaches. ISC organoids have also provided a platform for studying intestinal diseases and testing personalized therapies. This comprehensive review covers the anatomical composition, physiological regulation, ISC biomarker studies, contribution to intestinal disorder pathogenesis and potential therapeutic implications of the ISC niche.

Genetics and biology of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) poses a grim prognosis for patients. Recent multidisciplinary research efforts have provided critical insights into its genetics and tumor biology, creating the foundation for rational development of targeted and immune therapies. Here, we review the PDAC genomic landscape and the role of specific oncogenic events in tumor initiation and progression, as well as their contributions to shaping its tumor biology. We further summarize and synthesize breakthroughs in single-cell and metabolic profiling technologies that have illuminated the complex cellular composition and heterotypic interactions of the PDAC tumor microenvironment, with an emphasis on metabolic cross-talk across cancer and stromal cells that sustains anabolic growth and suppresses tumor immunity. These conceptual advances have generated novel immunotherapy regimens, particularly cancer vaccines, which are now in clinical testing. We also highlight the advent of KRAS targeted therapy, a milestone advance that has transformed treatment paradigms and offers a platform for combined immunotherapy and targeted strategies. This review provides a perspective summarizing current scientific and therapeutic challenges as well as practice-changing opportunities for the PDAC field at this major inflection point.

The Prognostic Value and Immunotherapeutic Characteristics of GFPT2 in Pan-cancer.

The purpose of this study is to investigate the underlying relationship of diagnosis and therapy between glutamine-fructose-6-phosphate transaminase 2 (GFPT2) and various cancers. The Cancer Genome Atlas (TCGA) database was utilized to get gene expression RNAseq and clinical data for 33 tumors. The immunotherapeutic cohorts, including GSE35640, GSE78220, GSE67501, GSE181815, and IMvigor210, were derived from the Gene Expression Omnibus database (GEO) and a previously released article. Differential expression analysis of GFPT2 was performed using several clinical factors, and prognostic analysis was performed using Cox proportional hazard regression. In addition, the Cell type Identification By Estimating Relative Subsets Of RNA transcripts (CIBERSORT) and the Estimation of STromal and Immune cells in MAlignant Tumor tissues utilizing Expression data (ESTIMATE) algorithms were used to investigate the connection between GFPT2 and the tumor microenvironment. This approach additionally incorporated dynamic immunological indicators, such as tumor mutational burden (TMB) and microsatellite instability (MSI). In addition, a correlation between GFPT2 expression and the effectiveness of anticancer drugs was plotted for discussion. GFPT2 expression significantly differed in 11 out of 33 cancers. Although the distinct correlation between GFPT2 expression and clinical parameters had no wide distribution in pan-cancer, it demonstrated the potential prognostic validity of gene expression. GFPT2 demonstrated a strong correlation with immune infiltration, immune modulators, and immunerelated biomarkers. Furthermore, a variance analysis demonstrated a significant relationship between GFPT2 and the efficacy of immunotherapy. In addition, GFPT2 was associated with increased sensitivity of drugs such as Olaparib and Lenvatinib and decreased sensitivity of drugs such as Nilotinib. Collectively, GFPT2 is potentially useful as a biomarker for prognostic prediction and immune infiltration in a variety of malignancies ,and could lead to exciting new approaches to personalized oncotherapy.

Mesenchymal stromal cells and platelet-riach fibrin membrane for the treatment of osteochondral defect in the rabbit

Cartilage has limited self-repair ability due to its complex structure and chondrocytes' relatively low metabolic activities. Functional repair of articular cartilage defects is a significant challenge for cartilage tissue engineering. Mesenchymal stromal cells (MSC) and platelet-rich fibrin membrane (PRFM) in repairing damaged articular cartilage in rabbit. They were subjected to osteochondral lesion and randomly into five groups: Group A, evaluated immediately after injury; Group B, natural evolution the injury; Group C, MSC; Group D, PRFM and Group E, MSC+ PRFM. Animals in Group A were euthanized after removing the cartilaginous flap, while animals in Groups B, C, D, and E were euthanized 60 days. The regeneration of the lesion was evaluated by analyzing its residual extension, as well as the density of chondrocytes and chondroblasts in the regenerated tissue adjacent to the lesion. Results, the Group E (MSC + PRFM) showed a greater reduction in the lesion size and a greater density of chondrocytes and chondroblasts in the regenerated and adjacent tissue compared to the other groups. Our results indicate that the combination of MSC and PRFM can successfully resurface the defect with cartilage and restore the subchondral bone in the specie studied, being effective in reducing hyaline cartilage defects; however, the combination of MSC and PRFM products might be more or less appropriate for treating different types of tissues and pathologies. The clinical efficacy of PRP remains under debate. Therefore, further research is needed at both the basic science and clinical levels.

Extracellular vesicles from cartilage progenitors stimulate type II collagen expression and wound healing in meniscal cells.

Knee meniscus tearing is a common orthopaedic injury that can heal poorly if left untreated, increasing the risk of post-traumatic Osteoarthritis. Intraarticular injection of human cartilage-derived progenitor cells (CPCs) has been shown to promote meniscus healing after injury. However, the mechanism by which CPCs stimulated this effect was unclear. The purpose of this study was to determine the paracrine effects that CPC-derived extracellular vesicles (EVs) have on native meniscal cells during healing. EVs from human CPCs and marrow-derived stromal cells were isolated via ultracentrifugation. EVs produced by each cell type were quantified, and their sizes were determined via NanoSight. EV protein expression was characterized via western blot. Meniscal fibrochondrocyte cellular metabolic activity (as an indicator of cell viability and proliferation) following treatment with EVs, was quantified using MTT and ATP assays. A 2D wound healing assay was used to determine the effects of treating inner meniscal fibrochondrocytes with EVs in a dose-dependent manner. Gene expression analysis for chondrogenesis genes was performed via RT-qPCR on inner meniscal fibrochondrocytes following treatment with EVs. Our results showed that CPCs produced a wide size range of EVs expressing CD9, CD81, and HSP70. Treatment of inner meniscal fibrochondrocytes with CPC-EVs improved 2D wound healing, in comparison to EVs isolated from marrow-derived stromal cell controls. CPC-EV treatment increased Type II Collagen mRNA expression in inner meniscal fibrochondrocytes. These findings demonstrate that CPC-EVs stimulate chondrogenic matrix production and wound healing in meniscal cells at the optimal dose of 1.0 × 107 particles/mL, significantly outperforming the effects of marrow stromal cell-derived EVs.

Titanium Surface Synergy: Strontium Incorporation and Controlled Disorder Nanotopography Optimize Osteoinduction.

Osteoporotic fractures and arthritis represent a major socioeconomic health burden. Fragility fracture fixation and joint replacement are often undertaken using titanium (Ti) or Ti alloy implants. Ideally these should induce bone formation and reduce osteoclast formation. Nanoscale topographies are potent inducers of osteogenesis, and strontium (Sr) has both osteogenic and antiosteoclastic effects. We incorporated strontium into a titanium surface with an osteogenic disordered nanoscale topography. The surface comprises 120 nm diameter, 100 nm deep pits in a near-square order with deliberate offset from the center pit position up to ±50 nm, providing a pattern with an average center-center pit spacing of 300 nm (called near-square 50, NSQ50). Several surfaces were assessed, including NSQ50 alone, strontium incorporated alone, and combined, compared with control surfaces. We assessed the surfaces using a human bone marrow stromal cell (BMSC)/ bone marrow hematopoietic cell (BHSC) coculture capable of osteogenesis and osteoclastogenesis. The samples eluted Sr over long-term culture, and uptake of Sr was better with eluted Sr than with Sr added to the culture media. The NSQ50 pattern in Ti was osteogenic, and addition of Sr elution increased osteogenesis further for both flat and NSQ50 samples. Interestingly, BMSCs on all Ti samples did not secrete the receptor activator of nuclear factor kappa-Β ligand (RANKL) or macrophage colony-stimulating factor (M-CSF) while secreting osteoprotegrin (OPG) at high levels. This meant that no osteoclast formation was observed on any Ti surface. Therefore, using Sr-incorporated nanotopographical imprinting, we generated highly osteogenic Ti surfaces that inhibited osteoclast formation.

Endothelin-1 receptor blockade impairs invasion patterns in engineered 3D high-grade serous ovarian cancer tumoroids.

High-grade serous ovarian cancer (HG-SOC), accounting for 70-80% of ovarian cancer deaths, is characterized by a widespread and rapid metastatic nature, influenced by diverse cell types, cell-cell interactions, and acellular components of the tumor microenvironment (TME). Within this tumor type, autocrine and paracrine activation of the endothelin-1 receptors (ET-1R), expressed in tumor cells and stromal components, drives metastatic progression. The lack of three-dimensional models that faithfully recapitulate the unique HG-SOC TME has been the bottleneck in performing drug screening for personalized medicine. Herein, we developed HG-SOC tumoroids by engineering a dense central artificial cancer mass (ACM) containing HG-SOC cells, nested within a compressed hydrogel recapitulating the stromal compartment comprising type I collagen, laminin, fibronectin, and stromal cells (fibroblasts and endothelial cells). ET-1-stimulated HG-SOC cells in the tumoroids showed an altered migration pattern and formed cellular aggregates, mimicking micrometastases that invaded the stroma. Compared to control cells, ET-1-stimulated tumoroids showed a higher number of invasive bodies, which were reduced by treatment with the dual ET-1 receptor (ET-1R) antagonist macitentan. In addition, ET-1 increased the size of the invading aggregates compared to control cells. This study establishes an experimental 3D multicellular model eligible for mechanical research, investigating the impact of matrix stiffness and TME interactions, which will aid drug screening to guide therapeutic decisions in HG-SOC patients.

Dissecting L-glutamine metabolism in acute myeloid leukemia: single-cell insights and therapeutic implications

BackgroundAcute myeloid leukemia (AML) is a rapidly progressing blood cancer. The prognosis of AML can be challenging, emphasizing the need for ongoing research and innovative approaches to improve outcomes in individuals affected by this formidable hematologic malignancy.MethodsIn this study, we used single-cell RNA sequencing (scRNA-seq) from AML patients to investigate the impact of L-glutamine metabolism-related genes on disease progression.ResultsOur analysis revealed increased glutamine-related activity in CD34 + pre-B cells, suggesting a potential regulatory role in tumorigenesis and AML progression. Furthermore, intercellular communication analysis revealed a significant signaling pathway involving macrophage migration inhibitory factor signaling through CD74 + CD44 within CD34 + pre-B cells, which transmit signals to pre-dendritic cells and monocytes. Ligands for this pathway were predominantly expressed in stromal cells, naïve T cells, and CD34 + pre-B cells. CD74, the pertinent receptor, was predominantly detected in a variety of cellular components, including stromal cells, pre-dendritic cells, plasmacytoid dendritic cells, and hematopoietic progenitors. The study’s results provide insights into the possible interplay among these cell types and their collective contribution to the pathogenesis of AML. Moreover, we identified 10 genes associated with AML prognosis, including CCL5, CD52, CFD, FABP5, LGALS1, NUCB2, PSAP, S100A4, SPINK2, and VCAN. Among these, CCL5 and CD52 have been implicated in AML progression and are potential therapeutic targets.ConclusionsThis thorough examination of AML biology significantly deepens our grasp of the disease and presents pivotal information that could guide the creation of innovative treatment strategies for AML patients.

Primary osteosarcoma of the breast during lactation: a case report and literature review

Primary osteosarcoma of the breast (POB) is an aggressive and exceedingly rare tumor, and cases with onset during lactation are extremely rare. The exact mechanism of POB development remains unclear. They may originate from totipotent mesenchymal cells in the breast stroma or may be the result of neoplastic transformation of prior breast lesions. Here, we present the case of a 40-year-old Chinese woman who was found with a palpable tumor measuring approximately 3 cm in diameter in her right breast while breastfeeding 4 months post-partum. The lactating woman was misdiagnosed with lactational mastitis during her initial visit to a community hospital. However, due to negative bacterial cultures and ineffective anti-infective treatment, later on the patient was taken to a more advanced hospital where a tissue biopsy was taken. The superior hospital considered that it might be a malignant tumor and performed local excision of the breast mass, leading to a final pathological diagnosis of POB. This is the first reported case of primary osteosarcoma during breastfeeding. We hope that this case report will improve readers’ understanding of the diagnosis and differential diagnosis of POB, especially for patients with atypical clinical symptoms and imaging findings, which should not be taken lightly.

Epicardial Adipocytes in Cardiac Pathology and Healing.

Implications of epicardial adipose tissue (EAT) on the development of coronary artery disease (CAD) have garnered recent attention. Located between the myocardium and visceral pericardium, EAT possesses unique morphological and physiological contiguity to the heart. The transcriptome and secretome of EAT differ from that of other fat stores in the body. Physiologically, EAT protects the adjacent myocardium through its brown-fat-like thermogenic function and rapid fatty acid oxidation. However, EAT releases pro-inflammatory mediators acting on the myocardium and coronary vessels, thus contributing to the development and progression of cardiovascular diseases (CVD). Furthermore, EAT-derived mesenchymal stromal cells indicate promising regenerative capabilities that offer novel opportunities in cell-based cardiac regeneration. This review aims to provide a comprehensive understanding and unraveling of EAT mechanisms implicated in regulating cardiac function and regeneration under pathological conditions. A holistic understanding of the multifaceted nature of EAT is essential to the future development of pharmacological and therapeutic interventions for the management of CVD.

The VEGF-Mediated Cytoprotective Ability of MIF-Licensed Mesenchymal Stromal Cells in House Dust Mite-Induced Epithelial Damage.

Enhancing mesenchymal stromal cell (MSC) therapeutic efficacy through licensing with proinflammatory cytokines is now well established. We have previously shown that macrophage migration inhibitory factor (MIF)-licensed MSCs exerted significantly enhanced therapeutic efficacy in reducing inflammation in house dust mite (HDM)-driven allergic asthma. Soluble mediators released into the MSC secretome boast cytoprotective properties equal to those associated with the cell itself. In asthma, epithelial barrier damage caused by the inhalation of allergens like HDM drives goblet cell hyperplasia. Vascular endothelial growth factor (VEGF) plays a pivotal role in the repair and maintenance of airway epithelial integrity. Human bone marrow-derived MSCs expressed the MIF receptors CD74, CXCR2, and CXCR4. Endogenous MIF from high MIF expressing CATT7 bone marrow-derived macrophages increased MSC production of VEGF through the MIF CXCR4 chemokine receptor, where preincubation with CXCR4 inhibitor mitigated this effect. CATT7-MIF licensed MSC conditioned media containing increased levels of VEGF significantly enhanced bronchial epithelial wound healing via migration and proliferation in vitro. Blocking VEGFR2 or theuse of mitomycin C abrogated this effect. Furthermore, CATT7-MIF MSC CM significantly decreased goblet cell hyperplasia after the HDM challenge in vivo. This was confirmed to be VEGF-dependent, as the use of anti-human VEGF neutralising antibody abrogated this effect. Overall, this study highlights that MIF-licenced MSCs show enhanced production of VEGF, which has the capacity to repair the lung epithelium.

Stem cell transplantation extends the reproductive life span of naturally aging cynomolgus monkeys

The ovary is crucial for female reproduction and health, as it generates oocytes and secretes sex hormones. Transplantation of mesenchymal stem cells (MSCs) has been shown to alleviate pathological ovarian aging. However, it is unclear whether MSCs could benefit the naturally aging ovary. In this study, we first examined the dynamics of ovarian reserve of Chinese women during perimenopause. Using a naturally aging cynomolgus monkey (Macaca fascicularis) model, we found that transplanting human embryonic stem cells-derived MSC-like cells, which we called M cells, into the aging ovaries significantly decreased ovarian fibrosis and DNA damage, enhanced secretion of sex hormones and improved fertility. Encouragingly, a healthy baby monkey was born after M-cell transplantation. Moreover, single-cell RNA sequencing analysis and in vitro functional validation suggested that apoptosis, oxidative damage, inflammation, and fibrosis were mitigated in granulosa cells and stromal cells following M-cell transplantation. Altogether, these findings demonstrate the beneficial effects of M-cell transplantation on aging ovaries and expand our understanding of the molecular mechanisms underlying ovarian aging and stem cell-based alleviation of this process.