Stem cells and development最新文献

Amelogenin, the primary protein of the enamel matrix, has long been implicated in regulating crystal nucleation, growth, and spatial organization during tooth development. This study investigates how the absence of amelogenin affects enamel structure and mineralization. Using amelogenin knockout mice, we examine its role in maintaining enamel integrity, modulating ameloblast vesicle dynamics, and facilitating calcium ion transport through specific channels to the enamel surface. The goal is to uncover the mechanistic contributions of amelogenin to enamel biomineralization and its broader implications for dental tissue engineering and pathology. Our study demonstrates that the absence of amelogenin leads to profound disruptions in enamel formation and mineral transport. In amelogenin-null mice, the typical enamel layer was absent and replaced by peg-like, tapered mineral structures. These pegs stained positively for calcium (via alizarin red) and inorganic phosphate (via von Kossa's method), indicating aberrant mineral deposition. Electron diffraction revealed that the pegs contained bundles of thin, parallel-aligned crystals with patterns consistent with calcium hydroxyapatite, confirming their mineralized nature. At the cellular level, ameloblasts in wild-type mice displayed large, bilayered vesicles (∼200 nm in diameter) at their apical poles, containing inorganic phosphate as detected by modified submicroscopic von Kossa staining. In contrast, amelogenin-deficient ameloblasts lacked both the bilayer membrane structure and phosphate labeling within these vesicles, suggesting disrupted vesicular transport and ion packaging. Further, in vivo calcium labeling with Fluo-4 showed successful apical transport of calcium to the enamel surface in wild-type mice. However, in the absence of amelogenin, calcium was aberrantly retained at the basal ameloblast pole and in the stratum intermedium. This mislocalization correlated with altered expression and distribution of intracellular calcium channel proteins, as shown by immunoreactivity. Together, these findings expand the functional role of amelogenin beyond structural organization during early enamel crystal formation. They reveal a previously underappreciated role in mediating vesicle architecture, phosphate loading, and directional calcium ion transport essential for proper enamel mineralization.

Schizophrenia, a complex neuropsychiatric disorder, exhibits a wide range of genetic diversity. Multiple Genome-Wide Association Studies have identified several Copy Number Variations (CNVs) associated with schizophrenia. One of the significant CNVs, comprising an intragenic deletion of the CNTNAP2 gene, has been associated with various neuro-developmental and neuro-psychiatric disorders. However, the molecular mechanism leading to the pathogenesis of schizophrenia remained unclear. In this study, we report a 7q35-36.1del encompassing the entire CNTNAP2 gene in two affected siblings. Human induced Pluripotent Stem Cells (hiPSCs) were generated from both affected individuals. Neurons derived from the patient's hiPSCs lines have revealed that the dendritic length and arborization, spine number and density, soma area and volume were decreased in the patient's neurons, while axon length was increased. Further classifying the dendritic spines, it was observed that the percentage of filopodia spines was increased, whereas stubby, mushroom, and long thin spines were decreased in the patient's neurons. Transcriptomics of hiPSCs-derived neurons has revealed eight significantly dysregulated genes that interact directly or indirectly with CNTNAP2. Of these eight genes, schizophrenia-associated genes, PADI2 and LHX2, were observed to be significantly dysregulated. Overall, this study has identified abnormalities in neuronal architecture in hiPSCs-derived patients' neurons harboring CNTNAP2 gene deletion, confirming the disease pathophysiology of schizophrenia.

Mesenchymal stem cells (MSCs) are adult stem cells with extensive differentiation potential, sourced from bone marrow, adipose tissue, umbilical cord blood, and other tissues. MSCs from different origins exhibit distinct functional characteristics. These cells have demonstrated therapeutic efficacy in various neurological disorders, primarily by modulating immune responses, promoting neovascularization, and aiding neural circuit reconstruction. Notably, the strong proangiogenic properties of MSCs play a crucial role in disease treatment and regression. This review focuses on the application of MSCs and their derivatives in neurological disorders, primarily exploring strategies to enhance their angiogenic effects, including pharmacological interventions, genetic modification, modulation of the culture environment, and the application of novel materials. Furthermore, the article prospects the potential application of MSC-mediated angiogenesis in the treatment of neurological disorders, specifically in the surgical management of ischemic cerebrovascular diseases.

Effective treatment options for steroid-refractory acute graft-versus-host disease (SR-aGVHD) remain limited. Mesenchymal stromal cells (MSCs) offer a promising therapeutic approach, but the optimal administration protocol is undefined. This retrospective cohort study investigated the impact of MSC infusion frequency on outcomes in patients with grade III-IV SR-aGVHD who received umbilical cord-derived MSCs either once weekly (n = 25) or three times weekly (n = 18). The primary endpoints were overall response rate (ORR) and complete response (CR) at 28 days, and secondary endpoints included overall survival (OS) and changes in lymphocyte subsets. The thrice-weekly group demonstrated significantly superior ORR (77.8% vs. 48.0%, P < 0.05) and CR rates (55.6% vs. 20.0%, P < 0.05), with a particularly notable benefit in gastrointestinal aGVHD (ORR: 73.3% vs. 35.0%, P < 0.05). Immunological analysis showed a more rapid and profound decline in CD3⁺CD8⁺ T cells in the thrice-weekly group (nadir: 21.16% vs. 52.09%, P < 0.05; time to nadir: 10 vs. 21 days, P < 0.05). With a median follow-up of 423 days, the thrice-weekly regimen was associated with significantly improved 2-year OS (78.1% vs. 47.4%, P < 0.05). Despite the limitations of a retrospective design, these findings suggest that increased MSC infusion frequency might be associated with improved therapeutic efficacy and survival in severe SR-aGVHD. However, the potential confounding effect of cumulative dose cannot be excluded, and these results warrant validation in prospective randomized trials.

Neural crest (NC) cells are a transient population of migratory multipotent cells that give rise to a wide variety of derivatives, including neurons, glial cells, Schwann cells, melanocytes, endocrine cells, smooth muscle cells, and the skeletal and connective tissue components of the craniofacial complex. Although the multipotency of NC cells is generally considered to be transient during the early stages of NC formation, accumulating evidence indicates that these cells retain their multipotent characteristics during embryonic migration. Moreover, multipotent NC stem-like cells (NCSCs) persist even within target tissues in the fetal and adult stages. Recent advances in high-throughput and integrative transcriptomic analyses have provided a comprehensive understanding of the genetic and molecular profiles of NC cells. These studies have revealed that NC cells exhibit remarkable transcriptional diversity and simultaneously express genes associated with pluripotency, lineage specification, and differentiation, underscoring their intrinsic plasticity. The multipotency and plasticity of NC cells and NCSCs thus represent a compelling field of study with significant implications for developmental biology and regenerative medicine. In this review, we summarize advances in research on NC cells and multipotent NCSCs as well as the transcription factors that maintain the multipotency of NC cells.

Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy characterized by the rapid proliferation of abnormal myeloid cells in the bone marrow. Despite advances in chemotherapy and targeted therapies, drug resistance and high relapse rates remain the major challenges in AML treatment. Accumulating evidence indicates that bone marrow mesenchymal stem cells (MSCs)-mediated microenvironment changes play a crucial role in the pathogenesis of AML and may contribute to the therapeutic challenges of current treatment strategies. In this study, we further characterized the role and revealed the molecular mechanism of AML-derived MSCs (AML-MSCs) in AML pathogenesis. We found that AML-MSCs significantly promoted AML cell proliferation and inhibited apoptosis, primarily through direct cell-to-cell contact. Bioinformatics analysis of multiple sequencing datasets revealed that decorin (DCN), encoding a core extracellular matrix protein, is significantly upregulated in AML-MSCs. DCN could enhance AML cell viability through functional interplay with matrix metalloproteinase-2 (MMP2) in AML cells. Both inhibition of DCN in AML-MSCs and MMP2 in AML cells significantly attenuated the supportive effect of AML-MSCs on AML cells. These findings provide novel insights into the role of MSC-mediated bone marrow microenvironment remodeling in AML pathogenesis and highlight DCN and MMP2 as potential therapeutic targets for AML treatment.

Intrauterine adhesion (IUA), a prevalent cause of female infertility and recurrent pregnancy loss, is characterized by endometrial trauma and progressive fibrosis. Current treatment modalities, including hysteroscopic adhesiolysis and hormone decidual multipotent mesenchymal stromal cells (DMSCs), a unique subset of stromal cells derived from the endometrium, exhibit strong multipotent differentiation capabilities, immunomodulatory properties, and low immunogenicity. These features enable DMSCs to facilitate endometrial regeneration, restore intrauterine immune homeostasis, and attenuate fibrosis, offering a compelling therapeutic strategy for IUA. Recent preclinical studies have demonstrated promising regenerative outcomes, yet the clinical application of DMSCs remains constrained by challenges such as limited cell availability, variability in therapeutic efficacy, and concerns regarding long-term safety. This review provides a comprehensive overview of the current progress in DMSC-based therapy for IUA, highlights its mechanistic advantages, and discusses critical obstacles and future directions for successful clinical translation.

Human induced pluripotent stem cells (hiPSC) are an invaluable resource for investigating the molecular mechanisms regulating cell fate specification during brain development. However, most directed differentiation methods exhibit significant cell fate heterogeneity and require several months to become functional. To address this challenge, we developed a green fluorescent protein (GFP) reporter system in hiPSC by targeting the genomic locus of Forebrain Enriched Zinc Finger 2 (FEZF2), which encodes a transcription factor essential for the fate specification of sub-cerebral projection neurons (SCPN) during forebrain development. Using this FEZF2-GFP reporter hiPSC line, we optimized a directed differentiation protocol to rapidly and efficiently generate pallial progenitors and glutamatergic neuronal subgroups after 3 weeks. Through fluorescence activated cell sorting for both GFP and CD200, isolated post-mitotic SCPN immediately displayed electrophysiological properties and formed glutamatergic synapses within 4 additional weeks of in vitro cell culture. Co-culture with hiPSC-derived spinal motor neurons further enhanced these electrophysiological characteristics, improved viability, and increased synapse formation in SCPN. This study presents a streamlined and effective strategy to generate, isolate, and characterize human motor neuron circuits, providing insights into the molecular determinants regulating synaptogenesis and functional maturation.

Hematopoietic stem cell (HSC) transplantation improves stroke outcomes. The mechanism of HSC transplantation involves delivering metabolites, such as glucose, to injured cerebral endothelial cells via gap junctions. To mimic HSC function, we prepared glucose-encapsulated liposomes functionalized with sialyl Lewis X on their surfaces and evaluated their therapeutic effects in a murine stroke model. As a result, liposomes with sialyl Lewis X accumulated in both the poststroke and contralateral cortices, whereas those without sialyl Lewis X showed no accumulation. Administration of glucose-encapsulated liposomes with sialyl Lewis X improved stroke outcomes and enhanced cerebral blood flow. Our findings indicate that liposome therapy could serve as a promising alternative to stem cell therapy for stroke.