Remodeling Of Niche Research Articles

Consequences of the perivascular niche remodeling for tumoricidal T-cell trafficking into metastasis of ovarian cancer.

The treatment-induced activation level within the perivascular tumor microenvironment (TME) that supports T-cell trafficking and optimal T-cell differentiation is unknown. We investigated the mechanisms by which inflammatory responses generated by tumor-specific T cells delivered to ovarian tumor-bearing mice alone or after oncolytic vaccinia virus-driven immunogenic cancer cell death affect antitumor efficacy. Analyses of the perivascular TME by spatially resolved omics technologies revealed reduced immunosuppression and increased tumoricidal T-cell trafficking and function after moderate inflammatory responses driven by a CXCR4 antagonist-armed oncolytic virus. Neither weak nor high inflammation created a permissive TME for T-cell trafficking. Notably, treatment-mediated differences in T-cell effector programs acquired within the perivascular TME contrasted with comparable antigenic priming in the tumor-draining lymph nodes regardless of the activation mode of antigen-presenting cells. These findings provide new insights into combinatorial treatment strategies that enable tumor-specific T cells to overcome multiple barriers for enhanced trafficking and control of tumor growth. .

Niche remodeling during aging process

Niche remodeling during aging process

Spatially Resolved Niche and Tumor Microenvironmental Alterations in Gastric Cancer Peritoneal Metastases

Background and aimsPeritoneal metastasis (PM) in gastric cancer (GC) is associated with poor prognosis and significant morbidity. We sought to understand the genomic, transcriptomic, and tumor microenvironment (TME) features that contribute to peritoneal organotropism in GC. MethodsWe conducted a comprehensive multi-omic analysis of 548 samples from 326 patients, including primary tumors, matched normal tissues, peritoneal metastases, and adjacent-normal peritoneal tissues. We employed whole exome sequencing, whole transcriptome sequencing, and digital spatial profiling to investigate molecular alterations, gene expression patterns, and TME characteristics associated with PM. ResultsOur analysis identified specific genomic alterations in primary tumors, including mutations in ELF3, CDH1, and PIGR, and TME signatures, such as stromal infiltration and M2 macrophage enrichment, associated with increased risk of PM. We observed distinct transcriptional programs and immune compositions in GCPM compared to liver metastases, highlighting the importance of the TME in transcoelomic metastasis. We found differential expression of therapeutic targets between primary tumors and PM, with lower CLDN18.2 and FGFR2b expression in PM. We unravel the roles of the TME in niche reprogramming within the peritoneum, and provide evidence of pre-metastatic niche conditioning even in early GC without clinical PM. These findings were further validated using a humanized mouse model, which demonstrated niche remodeling in the peritoneum during transcoelomic metastasis. ConclusionOur study provides a comprehensive molecular characterization of GCPM and unveils key biological principles underlying transcoelomic metastasis. The identified predictive markers, therapeutic targets, and TME alterations offer potential avenues for targeted interventions and improved patient outcomes.

HIF-2α inhibition disrupts leukemia stem cell metabolism and impairs vascular microenvironment to enhance chronic myeloid leukemia treatment

Leukemic stem cells (LSCs) in chronic myeloid leukemia (CML) contribute to treatment resistance and disease recurrence. Metabolism regulates LSCs, but the mechanisms remain elusive. Here, we show that hypoxia-inducible factor 2α (HIF-2α) is highly expressed in LSCs in mouse and human CML and increases after tyrosine kinase inhibitor (TKI) treatment. Deletion of HIF-2α suppresses disease progression, reduces LSC numbers, and enhances the efficacy of TKI treatment in BCL-ABL-induced CML mice. Mechanistically, HIF-2α deletion reshapes the metabolic profile of LSCs, leading to increased production of reactive oxygen species (ROS) and apoptosis in CML. Moreover, HIF-2α deletion decreases vascular endothelial growth factor (VEGF) expression, thereby suppressing neovascularization in the bone marrow of CML mice. Furthermore, pharmaceutical inhibition of HIF-2α by PT2399 attenuates disease progression and improves the efficacy of TKI treatment in both mouse and human CML. Overall, our findings highlight the role of HIF-2α in controlling the metabolic state and vascular niche remodeling in CML, suggesting it is a potential therapeutic target to enhance TKI therapy.

Enhanced homing of mesenchymal stem cells for in situ niche remodeling and bone regeneration

Enhanced homing of mesenchymal stem cells for in situ niche remodeling and bone regeneration

The footprint of gut microbiota in gallbladder cancer: a mechanistic review.

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system with the worst prognosis. Even after radical surgery, the majority of patients with GBC have difficulty achieving a clinical cure. The risk of tumor recurrence remains more than 65%, and the overall 5-year survival rate is less than 5%. The gut microbiota refers to a variety of microorganisms living in the human intestine, including bacteria, viruses and fungi, which profoundly affect the host state of general health, disease and even cancer. Over the past few decades, substantial evidence has supported that gut microbiota plays a critical role in promoting the progression of GBC. In this review, we summarize the functions, molecular mechanisms and recent advances of the intestinal microbiota in GBC. We focus on the driving role of bacteria in pivotal pathways, such as virulence factors, metabolites derived from intestinal bacteria, chronic inflammatory responses and ecological niche remodeling. Additionally, we emphasize the high level of correlation between viruses and fungi, especially EBV and Candida spp., with GBC. In general, this review not only provides a solid theoretical basis for the close relationship between gut microbiota and GBC but also highlights more potential research directions for further research in the future.

Abstract 257: Plasticity of preneoplastic cells drives esophageal squamous cell cancer initiation

Abstract Esophageal squamous cell carcinoma (ESCC) accounts for over 80% of esophageal cancer, with a poor prognosis mainly due to a lack of early-stage symptoms. Early detection of ESCC is challenging due to its origin in the basal cell layer and invasion into the lamina propria upon becoming neoplastic. Thus, understanding the transition mechanism from preneoplasia to neoplasia is crucial for early-stage detection of ESCC before dissemination. To dissect the mechanisms of ESCC preneoplasia and neoplasia, we utilized both spatial and temporal datasets of ESCC in conjunction with a genetically engineered organoid model. For spatial datasets, we conducted comparative analyses of single-cell transcriptomes from healthy esophageal tissues, normal tissue adjacent to cancer (NAC), and paired ESCC tumors to identify distinguishable preneoplastic cells. Notably, unlike normal or ESCC, NAC harbors a distinct preneoplastic cell cluster characterized by the exclusive expression of the CELF2 (CUGBP Elav-Like Family Member 2) gene, high gene copy number variations, cell hyperproliferation, and apoptosis, reminiscent of a 'crisis state'. Consistently, we detected a significant presence of CELF2 positive (+) cells at the stage of inflammation, a very early lesion preceding neoplasia in a temporal model of ESCC development. Copy number variations were also already abundant from the inflammation stage, as we observed in the NAC dataset. Interestingly, both spatial and temporal preneoplastic cells showed decreased scores of TP53 and CDKN2A signaling pathways, of which mutations are observed in 68% of ESCC patients. To recapitulate this phenotype, we employed genetically engineered esophageal organoids and found that the loss of Trp53 and Cdkn2a (PC) generated preneoplastic CELF2+ cells. Intriguingly, these preneoplastic CELF2+ cells exhibited remarkable cellular plasticity in two ways. Firstly, CELF2+ cells of PC display increased stemness mediated by SOX2-driven reprogramming with disrupted normal esophageal cell lineage. Second, CELF2+ cells of PC undergo epithelial-mesenchymal plasticity to generate fibroblast-like cells, releasing cytokines involved in immune remodeling. Consequently, preneoplastic CELF2+ cells developed significant tumors compared to CELF2-negative cells in transplantation assays. Our study identified preneoplastic CELF2+ cells driven by TP53 and CDKN2A loss as pivotal drivers in ESCC initiation via cell-autonomous (cellular reprogramming) as well as non-cell autonomous (immune niche remodeling) processes, proposing CELF2+ cells and their molecular signatures as potential biomarkers and therapeutic targets for early-stage ESCC. Citation Format: Kyung Pil Ko, Jie Zhang, Sohee Jun, Jae-Il Park. Plasticity of preneoplastic cells drives esophageal squamous cell cancer initiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 257.

Lactate Transporters Modulate Stromal Cell Remodeling in Myeloproliferative Neoplasms (MPN)

Introduction. Philadelphia-negative myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The diagnostic approach proposed by the World Health Organization (WHO) uses clinical features, bone marrow (BM) morphology, karyotype and molecular genetic tests to classify MPN subtypes. The BM morphology includes cellularity, erythropoiesis, and neutrophil granulopoiesis in context with specific features of megakaryocytes as well as the BM fiber content, especially in early-stage myelofibrosis that present with thrombocytosis and clinically mimic ET. Since alteration of hematopoiesis is constantly associated with profound modifications of the bone marrow (BM), we hypothesize that CD34+ cells from PMF can actively produce lactate and thus rewiring metabolism of immune cells and mesenchymal stromal cells (MSCs). In turn, this could favor immune evasion and remodeling of BM niche. Methods.Cell proliferation was assessed in vitro on primary MSCs, HS-5 cell line, and PBMC cells. Protein expression was performed by Western blot and immunofluorescence assay. The NCBI GEO database was used to select transcriptome datasets and to analyze gene expression in PMF patients. Cytokine detections were performed by Multiplex immunobead assay technology. An adult TPO-mimetic-induced PMF Zebrafish model was used for in vivo evaluation. An immunohistology assay was performed in MPN BM biopsies. Results.CD34+ cells from PMF patients significantly upregulated the lactate monocarboxylate transporters (MCT-1 and -4) compared to healthy CD34+ cells. Consistently, lactate concentration was higher in PMF sera compared to healthy controls. Since PMF patients showed an increased percentage of circulating immunosuppressive cells such as G- and M-MDSC and Treg, we incubated healthy peripheral blood mononucleated cells (PBMNCs) with PMF sera in the presence or absence of MCT1inhibitor (AZD3965) to evaluate the role of lactate in the expansion of these immunological subsets. We found an expansion of both Treg and M-MDSCs, which was reverted after blocking of circulating lactate by AZD3965. In order to study the effect of lactate in BM remodeling, we treated in vitro healthy MSCs with lactate (20 mM) for 24h. Interestingly, lactate induced a modification of extracellular matrix organization, as demonstrated by increased reticulin and collagen deposition and metalloproteases (MMP9, MMP2). Moreover, lactate increased calcium deposit and soluble osteogenic molecular signals (i.e. osteoprotegerin, osteonectin). These results also were obtained after incubation with PMF sera and were reverted after AZD3965 treatment. Since it has been demonstrated the role of cancer-associated fibroblast (CAF) in cancer development through ECM remodeling, we next evaluated the expression of CAF markers in MSCs after lactate exposure. α-SMA, FAP1, and TGFβ were found upregulated and this effect was reverted by AZD3965. Finally, we further confirmed these results in a Zebrafish animal model of PMF. Interestingly, in Zebrafish model we observed a reduction of MCT4 expression that was confirmed in the PBMNCs of the PMF patients. Conclusions. Inhibition of lactate metabolism may represent a strategy to inhibit cancer cells and contribute to restoring the anti-cancer immune response. Therefore, lactate metabolism may represent a promising target to counteract inflammation, osteosclerosis, and fibrosis in PMF patients.

Reduction in Lymphoid-Supporting Factors By Mesenchymal Stromal Cells Drives Myeloid-Biased Hematopoiesis at Middle Age

The bone marrow “niche” for hematopoietic stem cells (HSCs) encompasses various cell types, extracellular matrices and secreted factors that maintain the specialized functions of HSCs such as quiescence, self-renewal, and production of multipotent progenitor cells. In old age, changes in this niche contribute to dysfunction of HSCs and the hematopoietic system including increased inflammation and myeloid-biased molecular programs. We have observed that HSC and hematopoietic aging phenotypes become apparent by mid-age (Young et al. Cell Stem Cell 2021, Young et al. J Exp Med 2016), leading to the hypothesis that evaluating alterations in the niche at this stage would reveal the earliest changes initiating HSC aging. To test this hypothesis, we examined both the hematopoietic and non-hematopoietic compartments in individual middle-aged (12-14 months of age, n = 9) and compared them to young C57BL/6 mice (2-4 months of age, n = 5). Immunostaining of femurs showed an increase in sinusoid volume, vessel dysmorphia, and an increase in megakaryocyte abundance in the bone marrow of middle-aged mice. No alterations were observed in arterioles nor adipocyte volume. This data provides supporting evidence that a subset of HSC niche remodeling phenotypes observed in old age are present by mid-age. We then performed single-cell RNA-seq to comprehensively assess changes in abundance and transcriptomes of hematopoietic and non-hematopoietic cells at mid-age. Analysis of this data revealed significant expansion of HSCs in middle-aged mice. In the expanded HSC population, a reduction in B lymphoid differentiation signatures was observed without alterations in inflammation or myeloid differentiation signatures. Computational predictions suggested that the reduced B lymphopoiesis program in middle-aged HSCs resulted from decreased interaction with soluble factors produced by subsets of mesenchymal stromal cells (MSCs), rather than endothelial cells or other hematopoietic cell compartments. Specifically, reduced MSC-to-HSC interactions were linked to a decline in signaling mediated by adiponectin (ADIPOQ; Adipoq), stem cell factor (SCF; Kitl), midkine (MDK; Mdk), and insulin-like growth factor 1 (IGF1; Igf1). Among these, reductions in Kitl and Igf1 in MSCs were correlated with the loss of B lymphopoiesis programs in HSCs comparing individual middle-aged mice. To test the functional impact of the decline in Igf1 in MSCs on lymphopoiesis, we created three MSC-selective Igf1 conditional knockout mouse models using distinct Cre recombinases (Lepr-Cre, nestin-CreER and Prx1-CreER). In all three of these models, MSC-selective knockout of Igf1 reduced B lymphopoiesis resulting in myeloid-biased hematopoiesis, replicating hematopoietic aging phenotypes observed at middle age. These findings indicate that the decline in B lymphopoiesis from HSCs during aging is initiated by a reduction in lymphoid-supporting factors produced by MSCs in the bone marrow microenvironment, and this occurs independently of inflammation or activation of myeloid-promoting transcriptional programs in HSCs.

Differentiation potential of periodontal Col1+ cells under orthodontic force

Mechanical force often has clear effects on tissue niche remodeling. However, the changes in stem cells and their roles in clinical treatment remain unclear. Orthodontic tooth movement (OTM), the primary approach to treating dental-maxillofacial malformations, involves reconstruction of periodontal tissue. Herein, lineage tracing revealed that Col1+ cells are distributed in the periodontal ligament and are sensitive to mechanical forces during OTM. Immunofluorescence analysis confirms that Col1+ cells can differentiate into osteoblasts and fibroblasts under orthodontic force. Moreover, Col1+ cells may be involved in angiogenesis. These findings suggest that Col1+ cells play a crucial role in the mechanical remodeling of periodontal tissue during OTM and may serve as a valuable tool for studying the mechanism of OTM.

Transcriptional Targets of TWIST1 in Human Mesenchymal Stem/Stromal Cells Mechanistically Link Stem/Progenitor and Paracrine Functions.

Despite extensive clinical testing, mesenchymal stem/stromal cell (MSC)-based therapies continue to underperform with respect to efficacy, which reflects the paucity of biomarkers that predict potency prior to patient administration. Previously, we reported that TWIST1 predicts inter-donor differences in MSC quality attributes that confer potency. To define the full spectrum of TWIST1 activity in MSCs, the present work employed integrated omics-based profiling to identify a high-confidence set of TWIST1 targets, which mapped to cellular processes related to ECM structure/organization, skeletal and circulatory system development, interferon gamma signaling, and inflammation. These targets are implicated in contributing to both stem/progenitor and paracrine activities of MSCs indicating these processes are linked mechanistically in a TWIST1-dependent manner. Targets implicated in extracellular matrix dynamics further implicate TWIST1 in modulating cellular responses to niche remodeling. Novel TWIST1-regulated genes identified herein may be prioritized for future mechanistic and functional studies.

Different niches for stem cells carrying the same oncogenic driver affect pathogenesis and therapy response in myeloproliferative neoplasms

Aging facilitates the expansion of hematopoietic stem cells (HSCs) carrying clonal hematopoiesis-related somatic mutations and the development of myeloid malignancies, such as myeloproliferative neoplasms (MPNs). While cooperating mutations can cause transformation, it is unclear whether distinct bone marrow (BM) HSC-niches can influence the growth and therapy response of HSCs carrying the same oncogenic driver. Here we found different BM niches for HSCs in MPN subtypes. JAK–STAT signaling differentially regulates CDC42-dependent HSC polarity, niche interaction and mutant cell expansion. Asymmetric HSC distribution causes differential BM niche remodeling: sinusoidal dilation in polycythemia vera and endosteal niche expansion in essential thrombocythemia. MPN development accelerates in a prematurely aged BM microenvironment, suggesting that the specialized niche can modulate mutant cell expansion. Finally, dissimilar HSC-niche interactions underpin variable clinical response to JAK inhibitor. Therefore, HSC-niche interactions influence the expansion rate and therapy response of cells carrying the same clonal hematopoiesis oncogenic driver.

A Single-Cell Taxonomy Predicts Inflammatory Niche Remodeling to Drive Tissue Failure and Outcome in Human AML.

Tumor-promoting inflammation is considered an enabling characteristic of tumorigenesis, but mechanisms remain incompletely understood. By deciphering the predicted signaling between tissue-resident stem cells and their neoplastic counterparts with their environment, we identify inflammatory remodeling of stromal niches as a determinant of normal tissue repression and clinical outcomes in human AML. See related commentary by Lisi-Vega and Méndez-Ferrer, p. 349. This article is featured in Selected Articles from This Issue, p. 337.

Human umbilical cord blood-derived mesenchymal stem cells restored hematopoiesis by improving radiation induced bone marrow niche remodeling in rats

BackgroundFunctional hematopoiesis is governed by the bone marrow (BM) niche, which is compromised by radiotherapy, leading to radiation induced BM failure. The aim of this study was to demonstrate the radiation induced pathological remodeling of the niche and the efficacy of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in restoring hematopoiesis via improvement of the niche. MethodsThirty male Wistar rats were equally assigned to three groups: control (CON), irradiated (IR), and IR+hUCB‐MSCs. Biochemical, histopathological and immunohistochemical analyses were performed to detect collagen type III and IV, Aquaporin 1+ sinusoidal endothelial cells and immature hematopoietic cells, CD11c+ dendritic cells, Iba1+ macrophages, CD9+ megakaryocytes, Sca-1+, cKit+, CD133 and N-cadherin+ hematopoietic stem and progenitor cells, CD20+, Gr1+ mature hematopoietic cells, in addition to ki67+ proliferation, Bcl-2+ anti-apoptotic, caspase-3+ apoptotic, TNF-α+ inflammatory cells. Histoplanimetry data were statistically analyzed using the one-way analysis of variance followed by the post hoc Duncan’s test. Moreover, Pearson’s correlation was used to assess the correlation between various parameters. ResultsIn comparison to the IR group, the IR+hUCB-MSCs group showed restored cell populations and extracellular collagen components of the BM niche with significant increase in hematopoietic stem, progenitor, mature and proliferating cells, and a considerable decrease in apoptotic and inflammatory cells. Furthermore, highly significant correlations between BM niche and blood biochemical, histopathological, and immunohistochemical parameters were observed. ConclusionhUCB-MSCs restored functional hematopoiesis through amelioration of the BM niche components via reduction of oxidative stress, DNA damage, inflammation, and apoptosis with upregulation of cellular proliferation.

A Dual-Targeted Metal-Organic Framework Based Nanoplatform for the Treatment of Rheumatoid Arthritis by Restoring the Macrophage Niche.

Inflammatory infiltration and bone destruction are important pathological features of rheumatoid arthritis (RA), which originate from the disturbed niche of macrophages. Here, we identified a niche-disrupting process in RA: due to overactivation of complement, the barrier function of VSIg4+ lining macrophages is disrupted and mediates inflammatory infiltration within the joint, thereby activating excessive osteoclastogenesis and bone resorption. However, complement antagonists have poor biological applications due to superphysiologic dose requirements and inadequate effects on bone resorption. Therefore, we developed a dual-targeted therapeutic nanoplatform based on the MOF framework to achieve bone-targeted delivery of the complement inhibitor CRIg-CD59 and pH-responsive sustained release. The surface-mineralized zoledronic acid (ZA) of ZIF8@CRIg-CD59@HA@ZA targets the skeletal acidic microenvironment in RA, and the sustained release of CRIg-CD59 can recognize and prevent the complement membrane attack complex (MAC) from forming on the surface of healthy cells. Importantly, ZA can inhibit osteoclast-mediated bone resorption, and CRIg-CD59 can promote the repair of the VSIg4+ lining macrophage barrier to achieve sequential niche remodeling. This combination therapy is expected to treat RA by reversing the core pathological process, circumventing the pitfalls of traditional therapy.

Extracellular vesicle-mediated remodeling of the bone marrow microenvironment in myeloid malignancies.

Hematopoiesis is maintained and regulated by a bone marrow-specific microenvironment called a niche. In hematological malignancies, tumor cells induce niche remodeling, and the reconstructed niche is closely linked to disease pathogenesis. Recent studies have suggested that extracellular vesicles (EVs) secreted from tumor cells play a principal role in niche remodeling in hematological malignancies. Although EVs are emerging as potential therapeutic targets, the underlying mechanism of action remains unclear, and selective inhibition remains a challenge. This review summarizes remodeling of the bone marrow microenvironment in hematological malignancies and its contribution to pathogenesis, as well as roles of tumor-derived EVs, and provides a perspective on future research in this field.

Extracellular vesicles secreted by triple-negative breast cancer stem cells trigger premetastatic niche remodeling and metastatic growth in the lungs.

Tumor secreted extracellular vesicles (EVs) are potent intercellular signaling platforms. They are responsible for the accommodation of the premetastatic niche (PMN) to support cancer cell engraftment and metastatic growth. However, complex cancer cell composition within the tumor increases also the heterogeneity among cancer secreted EVs subsets, a functional diversity that has been poorly explored. This phenomenon is particularly relevant in highly plastic and heterogenous triple-negative breast cancer (TNBC), in which a significant representation of malignant cancer stem cells (CSCs) is displayed. Herein, we selectively isolated and characterized EVs from CSC or differentiated cancer cells (DCC; EVsCSC and EVsDCC , respectively) from the MDA-MB-231 TNBC cell line. Our results showed that EVsCSC and EVsDCC contain distinct bioactive cargos and therefore elicit a differential effect on stromal cells in the TME. Specifically, EVsDCC activated secretory cancer associated fibroblasts (CAFs), triggering IL-6/IL-8 signaling and sustaining CSC phenotype maintenance. Complementarily, EVsCSC promoted the activation of α-SMA+ myofibroblastic CAFs subpopulations and increased the endothelial remodeling, enhancing the invasive potential of TNBC cells in vitro and in vivo. In addition, solely the EVsCSC mediated signaling prompted the transformation of healthy lungs into receptive niches able to support metastatic growth of breast cancer cells.

Involvement of ACACA (acetyl-CoA carboxylase α) in the lung pre-metastatic niche formation in breast cancer by senescence phenotypic conversion in fibroblasts

BackgroundReprogramming of metabolism is strongly associated with the development of cancer. However, the role of metabolic reprogramming in the remodeling of pre-metastatic niche (PMN), a key step in metastasis, is still unknown. We aimed to investigate the metabolic alternation during lung PMN formation in breast cancer.MethodsWe assessed the transcriptomes and lipidomics of lung of MMTV-PyVT mice by microarray and liquid chromatography-tandem mass mass spectrometry before lung metastasis. The validation of gene or protein expressions was performed by quantitative real-time polymerase chain reaction or immunoblot and immunohistochemistry respectively. The lung fibroblasts were isolated from mice and then co-cultured with breast cancer to identify the influence of cancer on the change of lung fibroblasts in PMN.ResultsWe demonstrated changes in the lipid profile and several lipid metabolism genes in the lungs of breast cancer-bearing MMTV-PyVT mice before cancer spreading. The expression of ACACA (acetyl-CoA carboxylase α) was downregulated in the lung fibroblasts, which contributed to changes in acetylation of protein’s lysine residues and the synthesis of fatty acid. The downregulation of ACACA in lung fibroblasts triggered a senescent and inflammatory phenotypic shift of lung fibroblasts in both in vivo and in vitro models. The senescence-associated secretory phenotype of lung fibroblasts enabled the recruitment of immunosuppressive granulocytic myeloid-derived suppressor cells into the lungs through the production of CXCL1 in the lungs. Knock-in of ACACA prevented lung metastasis in the MMTV-PyVT mouse model, further supporting that ACACA was involved in the remodeling of the lung PMN.ConclusionsTaken together, these data revealed a mechanism by which ACACA downregulation directed the formation of an immunosuppressive lung PMN in breast cancer.

Stem cell niches functionalized strategies for organ regeneration and manufacturing

<p>Organ regeneration and manufacturing are promising new research directions in the life sciences. Stem cells and their niches, which exist in most adult organs, play a central role in organ development, homeostasis, and regeneration. Although considerable advances have been made in stem cell-mediated organ regeneration and manufacturing in recent decades, their clinical effectiveness remains unsatisfactory. Stem cell niches comprise a dynamic microenvironment that supports stem cells throughout their lifetime and are critical to stem cell fate. Based on recent research on stem cell niches, tremendous progress has been made in organ regeneration and manufacturing <i>in vivo</i> and <i>in vitro</i>. In this review, we discuss recent advances in the composition and function of stem cell niches during regeneration. We also discuss stem cell niche remodeling using cell-cell interaction, extracellular matrix (ECM) reconstruction, cell-ECM interaction, and key signaling-based niche strategies to promote endogenous tooth, gastrointestinal tract, and liver regeneration and its application in organoids and organoid-on-chip construction.</p>

Relationship between Tumor Infiltrating Immune Cells and Tumor Metastasis and Its Prognostic Value in Cancer.

Tumor metastasis is an important reason for the difficulty of tumor treatment. Besides the tumor cells themselves, the tumor microenvironment plays an important role in the process of tumor metastasis. Tumor infiltrating immune cells (TIICs) are one of the main components of TME and plays an important role in every link of tumor metastasis. This article mainly reviews the role of tumor-infiltrating immune cells in epithelial mesenchymal transformation, extracellular matrix remodeling, tumor angiogenesis and formation of pre-metastatic niche. The value of TIICs in the prognosis of cervical cancer, lung cancer and breast cancer was also discussed. We believe that accurate prognosis of cancer treatment outcomes is conducive to further improving treatment regimens, determining personalized treatment strategies, and ultimately achieving successful cancer treatment. This paper elucidates the relationship between tumor and TIICs in order to explore the function of immune cells in different diseases and provide new ideas for the treatment of cancer.