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Cells Apr 2024Glioblastoma is the most aggressive, malignant, and lethal brain tumor of the central nervous system. Its poor prognosis lies in its inefficient response to currently... (Review)
Review
Glioblastoma is the most aggressive, malignant, and lethal brain tumor of the central nervous system. Its poor prognosis lies in its inefficient response to currently available treatments that consist of surgical resection, radiotherapy, and chemotherapy. Recently, the use of mesenchymal stem cells (MSCs) as a possible kind of cell therapy against glioblastoma is gaining great interest due to their immunomodulatory properties, tumor tropism, and differentiation into other cell types. However, MSCs seem to present both antitumor and pro-tumor properties depending on the tissue from which they come. In this work, the possibility of using MSCs to deliver therapeutic genes, oncolytic viruses, and miRNA is presented, as well as strategies that can improve their therapeutic efficacy against glioblastoma, such as CAR-T cells, nanoparticles, and exosomes.
Topics: Humans; Glioblastoma; Mesenchymal Stem Cell Transplantation; Glioma; Brain Neoplasms; Mesenchymal Stem Cells
PubMed: 38607056
DOI: 10.3390/cells13070617 -
Acta Biomaterialia Sep 2023Osteoarthritis (OA) is a widespread clinical disease characterized by cartilage degeneration in middle-aged and elderly people. Currently, there is no effective... (Review)
Review
Osteoarthritis (OA) is a widespread clinical disease characterized by cartilage degeneration in middle-aged and elderly people. Currently, there is no effective treatment for OA apart from total joint replacement in advanced stages. Mesenchymal stem cells (MSCs) are a type of adult stem cell with diverse differentiation capabilities and immunomodulatory potentials. MSCs are known to effectively regulate the cartilage microenvironment, promote cartilage regeneration, and alleviate OA symptoms. As a result, they are promising sources of cells for OA therapy. Recent studies have revealed the presence of resident MSCs in synovial fluid, synovial membrane, and articular cartilage, which can be collected as knee joint-derived MSCs (KJD-MSC). Several preclinical and clinical studies have demonstrated that KJD-MSCs have great potential for OA treatment, whether applied alone, in combination with biomaterials, or as exocrine MSCs. In this article, we will review the characteristics of MSCs in the joints, including their cytological characteristics, such as proliferation, cartilage differentiation, and immunomodulatory abilities, as well as the biological function of MSC exosomes. We will also discuss the use of tissue engineering in OA treatment and introduce the concept of a new generation of stem cell-based tissue engineering therapy, including the use of engineering, gene therapy, and gene editing techniques to create KJD-MSCs or KJD-MSC derivative exosomes with improved functionality and targeted delivery. These advances aim to maximize the efficiency of cartilage tissue engineering and provide new strategies to overcome the bottleneck of OA therapy. STATEMENT OF SIGNIFICANCE: This research will provide new insights into the medicinal benefit of Joint resident Mesenchymal Stem Cells (MSCs), specifically on its cartilage tissue engineering ability. Through this review, the community will further realize promoting joint resident mesenchymal stem cells, especially cartilage progenitor/MSC-like progenitor cells (CPSC), as a preventive measure against osteoarthritis and cartilage injury. People and medical institutions may also consider cartilage derived MSC as an alternative approach against cartilage degeneration. Moreover, the discussion presented in this study will convey valuable information for future research that will explore the medicinal benefits of cartilage derived MSC.
Topics: Aged; Adult; Middle Aged; Humans; Tissue Engineering; Cartilage, Articular; Osteoarthritis; Mesenchymal Stem Cells; Knee Joint; Mesenchymal Stem Cell Transplantation
PubMed: 37481194
DOI: 10.1016/j.actbio.2023.07.024 -
Nature Protocols Aug 2023Developing models of human kidney tissue in vitro is an important challenge in regenerative nephrology research, given the paucity of novel and effective therapies in... (Review)
Review
Developing models of human kidney tissue in vitro is an important challenge in regenerative nephrology research, given the paucity of novel and effective therapies in kidney disease. However, the de novo generation of kidney tissues from human pluripotent stem cells (hPSCs) is challenging owing to the structural and functional complexity of the organ, as well its developmental origin from two distinct embryologic populations: the metanephric mesenchyme and the ureteric bud (UB). Directed differentiation strategies have been developed to generate kidney organoids containing nephron-like structures; we recently reported an efficient and practical method to generate UB tissues. Here, we describe a detailed step-by-step protocol for differentiation of hPSCs into three-dimensonal UB organoids that exhibit complex morphological development and the capacity to differentiate into functional collecting duct tissues. Over 3 d, hPSCs are induced into PAX2GATA3 pronephric (anterior) intermediate mesoderm fates in monolayer cultures at high efficiency. The cells are aggregated into three-dimensional spheroids, which then assemble and organize into nephric duct-like tissue over 4 d. When embedded into an extracellular matrix, the spheroids grow into UB organoids that recapitulate fetal branching morphogenesis for 1 week of culture. When switched to permissive conditions, the UB organoids spontaneously differentiate to form collecting duct principal cells. This approach provides robust and reproducible methods that can be readily adopted by users with basic experience in hPSC and organoid differentiation to generate UB tissues, which may be used to investigate human kidney development, model disease processes and catalyze further efforts in engineering functional kidney tissue.
Topics: Humans; Kidney; Organoids; Pluripotent Stem Cells; Cell Differentiation; Tissue Engineering
PubMed: 37460630
DOI: 10.1038/s41596-023-00847-2 -
Advanced Science (Weinheim,... Jul 2023Evidence suggests a unique association between bone aging and neurodegenerative/cerebrovascular disorders. However, the mechanisms underlying bone-brain interplay remain...
Evidence suggests a unique association between bone aging and neurodegenerative/cerebrovascular disorders. However, the mechanisms underlying bone-brain interplay remain elusive. Here platelet-derived growth factor-BB (PDGF-BB) produced by preosteoclasts in bone is reported to promote age-associated hippocampal vascular impairment. Aberrantly elevated circulating PDGF-BB in aged mice and high-fat diet (HFD)-challenged mice correlates with capillary reduction, pericyte loss, and increased blood-brain barrier (BBB) permeability in their hippocampus. Preosteoclast-specific Pdgfb transgenic mice with markedly high plasma PDGF-BB concentration faithfully recapitulate the age-associated hippocampal BBB impairment and cognitive decline. Conversely, preosteoclast-specific Pdgfb knockout mice have attenuated hippocampal BBB impairment in aged mice or HFD-challenged mice. Persistent exposure of brain pericytes to high concentrations of PDGF-BB upregulates matrix metalloproteinase 14 (MMP14), which promotes ectodomain shedding of PDGF receptor β (PDGFRβ) from pericyte surface. MMP inhibitor treatment alleviates hippocampal pericyte loss and capillary reduction in the conditional Pdgfb transgenic mice and antagonizes BBB leakage in aged mice. The findings establish the role of bone-derived PDGF-BB in mediating hippocampal BBB disruption and identify the ligand-induced PDGFRβ shedding as a feedback mechanism for age-associated PDGFRβ downregulation and the consequent pericyte loss.
Topics: Animals; Mice; Becaplermin; Hippocampus; Mice, Knockout; Mice, Transgenic; Pericytes; Proto-Oncogene Proteins c-sis; Receptor, Platelet-Derived Growth Factor beta
PubMed: 37102631
DOI: 10.1002/advs.202206938 -
Cell Reports Aug 2023Circular RNAs are generated by backsplicing and control cellular signaling and phenotypes. Pericytes stabilize capillary structures and play important roles in the...
Circular RNAs are generated by backsplicing and control cellular signaling and phenotypes. Pericytes stabilize capillary structures and play important roles in the formation and maintenance of blood vessels. Here, we characterize hypoxia-regulated circular RNAs (circRNAs) in human pericytes and show that the circular RNA of procollagen-lysine,2-oxoglutarate 5-dioxygenase-2 (circPLOD2) is induced by hypoxia and regulates pericyte functions. Silencing of circPLOD2 affects pericytes and increases proliferation, migration, and secretion of soluble angiogenic proteins, thereby enhancing endothelial migration and network capability. Transcriptional and epigenomic profiling of circPLOD2-depleted cells reveals widespread changes in gene expression and identifies the transcription factor krüppel-like factor 4 (KLF4) as a key effector of the circPLOD2-mediated changes. KLF4 depletion mimics circPLOD2 silencing, whereas KLF4 overexpression reverses the effects of circPLOD2 depletion on proliferation and endothelial-pericyte interactions. Together, these data reveal an important function of circPLOD2 in controlling pericyte proliferation and capillary formation and show that the circPLOD2-mediated regulation of KLF4 significantly contributes to the transcriptional response to hypoxia.
Topics: Humans; Hypoxia; Pericytes; RNA, Circular
PubMed: 37481725
DOI: 10.1016/j.celrep.2023.112824 -
International Journal of Molecular... Dec 2023In sports medicine, injuries related to the insertion of tendons into bones, including rotator cuff injuries, anterior cruciate ligament injuries and Achilles tendon... (Review)
Review
In sports medicine, injuries related to the insertion of tendons into bones, including rotator cuff injuries, anterior cruciate ligament injuries and Achilles tendon ruptures, are commonly observed. However, traditional therapies have proven to be insufficient in achieving satisfactory outcomes due to the intricate anatomical structure associated with these injuries. Adult bone marrow mesenchymal stem cells possess self‑renewal and multi‑directional differentiation potential and can generate various mesenchymal tissues to aid in the recovery of bone, cartilage, adipose tissue and bone marrow hematopoietic tissue. In addition, extracellular vesicles derived from bone marrow mesenchymal stem cells known as exosomes, contain lipids, proteins and nucleic acids that govern the tissue microenvironment, facilitate tissue repair and perform various biological functions. Studies have demonstrated that bone marrow mesenchymal stem cell‑derived exosomes can function as natural nanocapsules for drug delivery and can enhance tendon‑bone healing strength. The present review discusses the latest research results on the role of exosomes released by bone marrow mesenchymal stem cells in tendon‑bone healing and provides valuable information for implementing these techniques in regenerative medicine and sports health.
Topics: Humans; Exosomes; Tendons; Rotator Cuff Injuries; Wound Healing; Mesenchymal Stem Cells
PubMed: 37937691
DOI: 10.3892/ijmm.2023.5324 -
Aging Cell Nov 2023The craniofacial bones provide structural support for the skull and accommodate the vulnerable brain tissue with a protective cavity. The bone tissue undergoes constant...
The craniofacial bones provide structural support for the skull and accommodate the vulnerable brain tissue with a protective cavity. The bone tissue undergoes constant turnover, which relies on skeletal stem cells (SSCs) and/or mesenchymal stem cells (MSCs) and their niches. SSCs/MSCs and their perivascular niche within the bone marrow are well characterized in long bones. As for cranial bones, besides bone marrow, the suture mesenchyme has been identified as a unique niche for SSCs/MSCs of craniofacial bones. However, a comprehensive study of the two different cranial stem cell niches at single-cell resolution is still lacking. In addition, during the progression of aging, age-associated changes in cranial stem cell niches and resident cells remain uncovered. In this study, we investigated age-related changes in cranial stem cell niches via single-cell RNA sequencing (scRNA-seq). The transcriptomic profiles and cellular compositions have been delineated, indicating alterations of the cranial bone marrow microenvironment influenced by inflammaging. Moreover, we identified a senescent mesenchymal cell subcluster and several age-related immune cell subclusters by reclustering and pseudotime trajectory analysis, which might be closely linked to inflammaging. Finally, differentially expressed genes (DEGs) and cell-cell communications were analyzed during aging, revealing potential regulatory factors. Overall, this work highlights the age-related changes in cranial stem cell niches, which deepens the current understanding of cranial bone and suture biology and may provide therapeutic targets for antiaging and regenerative medicine.
Topics: Mice; Animals; Stem Cell Niche; Transcriptome; Skull; Mesenchymal Stem Cells; Stem Cells
PubMed: 37681346
DOI: 10.1111/acel.13980 -
The Journal of Experimental Medicine Feb 2024In dorsal root ganglia (DRG), macrophages reside close to sensory neurons and have largely been explored in the context of pain, nerve injury, and repair. However, we...
In dorsal root ganglia (DRG), macrophages reside close to sensory neurons and have largely been explored in the context of pain, nerve injury, and repair. However, we discovered that most DRG macrophages interact with and monitor the vasculature by sampling macromolecules from the blood. Characterization of the DRG vasculature revealed a specialized endothelial bed that transformed in molecular, structural, and permeability properties along the arteriovenous axis and was covered by macrophage-interacting pericytes and fibroblasts. Macrophage phagocytosis spatially aligned with peak endothelial permeability, a process regulated by enhanced caveolar transcytosis in endothelial cells. Profiling the DRG immune landscape revealed two subsets of perivascular macrophages with distinct transcriptome, turnover, and function. CD163+ macrophages self-maintained locally, specifically participated in vasculature monitoring, displayed distinct responses during peripheral inflammation, and were conserved in mouse and man. Our work provides a molecular explanation for the permeability of the blood-DRG barrier and identifies an unappreciated role of macrophages as integral components of the DRG-neurovascular unit.
Topics: Humans; Ganglia, Spinal; Endothelial Cells; Macrophages; Pericytes; Permeability
PubMed: 38117255
DOI: 10.1084/jem.20230675 -
Reproductive Medicine and Biology 2023The corpus cavernosum (CC) containing sinusoids plays fundamental roles for erection. Analysis of pathological changes in the erectile system is studied by recent... (Review)
Review
BACKGROUND
The corpus cavernosum (CC) containing sinusoids plays fundamental roles for erection. Analysis of pathological changes in the erectile system is studied by recent experimental systems. Various in vitro models utilizing genital mesenchymal-derived cells and explant culture systems are summarized.
METHODS
3D reconstruction of section images of murine CC was created. Ectopic chondrogenesis in aged mouse CC was shown by a gene expression study revealing the prominent expression of Sox9. Various experimental strategies utilizing mesenchyme-derived primary cells and tissue explants are introduced.
MAIN FINDINGS
Possible roles of Sox9 in chondrogenesis and its regulation by several signals are suggested. The unique character of genital mesenchyme is shown by various analyses of external genitalia (ExG) derived cells and explant cultures. Such strategies are also applied to the analysis of erectile contraction/relaxation responses to many signals and aging process.
CONCLUSION
Erectile dysfunction (ED) is one of the essential topics for the modern aged society. More comprehensive studies are necessary to reveal the nature of the erectile system by combining multiple cell culture strategies.
PubMed: 37663955
DOI: 10.1002/rmb2.12539 -
Acta Neuropathologica Communications Jul 2023Glioblastoma (GBM) is the most frequent malignant brain tumor, the relapse of which is unavoidable following standard treatment. However, the effective treatment for...
Glioblastoma (GBM) is the most frequent malignant brain tumor, the relapse of which is unavoidable following standard treatment. However, the effective treatment for recurrent GBM is lacking, necessitating the understanding of key mechanisms driving tumor recurrence and the identification of new targets for intervention. Here, we integrated single-cell RNA-sequencing data spanning 36 patient-matched primary and recurrent GBM (pGBM and rGBM) specimens, with 6 longitudinal GBM spatial transcriptomics to explore molecular alterations at recurrence, with each cell type characterized in parallel. Genes involved in extracellular matrix (ECM) organization are preferentially enriched in rGBM cells, and MAFK is highlighted as a potential regulator. Notably, we uncover a unique subpopulation of GBM cells that is much less detected in pGBM and highly expresses ECM and mesenchyme related genes, suggesting it may contribute to the molecular transition of rGBM. Further regulatory network analysis reveals that transcription factors, such as NFATC4 and activator protein 1 members, may function as hub regulators. All non-tumor cells alter their specific sets of genes as well and certain subgroups of myeloid cells appear to be physically associated with the mesenchyme-like GBM subpopulation. Altogether, our study provides new insights into the molecular understanding of GBM relapse and candidate targets for rGBM treatment.
Topics: Humans; Glioblastoma; Neoplasm Recurrence, Local; Gene Expression Profiling; Brain Neoplasms; Transcription Factors; Single-Cell Analysis
PubMed: 37525259
DOI: 10.1186/s40478-023-01613-x