Stem cells and development最新文献

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.

Vitamins are well known for their essential role in maintaining organismal homeostasis by directly influencing the function of a variety of cells. Among the tissues crucial for sustaining life is the bone marrow, where the highly organized and demanding daily production of billions of new blood cells occurs through a process known as hematopoiesis. At the apex of the hematopoietic hierarchy lie hematopoietic stem cells (HSCs), undifferentiated cells with multilineage potential that maintain themselves through extensive networks of cell-intrinsic and cell-extrinsic interactions. Despite considerable efforts to unravel these regulatory networks, the ways in which most vitamins influence the delicate balance of blood homeostasis remain largely unexplored. In this review, we summarize the current body of evidence linking vitamins to HSC metabolism and progeny, with a particular focus on preclinical findings that highlight the role of vitamins in maintaining hematopoietic tissue function. A deeper understanding of the contributions of vitamins to blood cell production could pave the way for innovative therapeutic approaches against hematological diseases.

This study investigates the effects of inflammation and orthodontic forces on the osteogenic differentiation of human dental follicle stem cells (hDFSCs) and their role in periodontal regeneration during orthodontic tooth movement (OTM) in periodontitis patients. Human DFSCs were exposed to interleukin-1β (IL-1β) and orthodontic compressive force (OCF). Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) assessed the expression of a disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS2), osteogenic markers, and ERK signaling components. ADAMTS2 overexpression (OE) plasmids and ERK activators were applied to explore the ADAMTS2/ERK signaling axis. A mouse periodontitis model with OTM was developed for in vivo evaluation. IL-1β and OCF downregulated ALP, RUNX2, and ERK pathway-related proteins and decreased ADAMTS2 expression. OE of ADAMTS2 significantly enhanced ERK phosphorylation (P < 0.05), promoting osteogenic differentiation of hDFSCs. ERK pathway activation with C16-PAF partially reversed the suppression of osteogenic differentiation induced by IL-1β and OCF. ADAMTS2/ERK axis components and osteogenic markers were reduced on the compressed side of periodontal tissues in the PD+OTM group (P < 0.05). These findings suggest that ADAMTS2 regulates the osteogenic differentiation of hDFSCs via the ERK signaling pathway under IL-1β and OCF stimulation, highlighting its potential as a therapeutic target for alveolar bone regeneration during OTM in periodontitis patients.

The cementum is a mineralized tissue that covers the tooth root and is necessary for anchoring periodontal ligament fibers to the teeth. During root development, dental follicle (DF) cells differentiate into cementoblasts, periodontal ligament fibroblasts, and osteoblasts to form the cementum, periodontal ligament, and bone, respectively. However, the mechanisms underlying these cell fate decisions remain unclear. Using scanning electron microscopy, we observed a basement membrane (BM)-like structure between the forming root dentin on the periodontal ligament side and the Hertwig's epithelial root sheath (HERS), as well as similar BM structures on the dentin surface after HERS removal. We hypothesized that these HERS-derived BM structures are involved in the differentiation of DF cells into cementoblasts and investigated the effect of basement membrane components (BMCs) on the differentiation of DF cells. Using a cell line (MDF) derived from DF cells of the incisors, we studied adhesion to hydroxyapatite. The undifferentiated MDF cells showed no adhesion. However, when coated with the BMC secreted by the HERS cell line (HERS02T), established from the first lower molars of tdTomato mice, MDF cells demonstrated increased initial adhesion, alkaline phosphatase activity, and calcification ability on hydroxyapatite. Additionally, we performed a comprehensive proteomic analysis of BMC secreted by HERS02T cells and-based on total spectral counts-identified three major proteins: laminin-332, tenascin-C, and periostin. These protein components were coated onto apatite-coated dishes and tested for the induction of MDF differentiation. The results showed that the coating significantly upregulated the expression of the cementoblast differentiation markers Sparcl1 and Ibsp. These results suggested that HERS may detach after BM formation on dentin surfaces. Subsequently, DF differentiate into cementoblasts using the BM when they migrate to the dentin surface.

Cells with renal progenitor cells characteristics are shed in urine. This study aimed to investigate whether these SIX2-positive urine-derived renal progenitor cells (UdRPC) have therapeutic potential in treating or managing acute to chronic kidney injuries, which are increasing worldwide and currently affect one in ten people. Human UdRPC were obtained from a 35-year-old woman, expanded, and characterized in vitro before being transplanted unilaterally under the renal capsule of mouse kidneys that had undergone ischemia reperfusion injury (IRI). The blood sera of the mice were examined for kidney injury markers such as blood-urea-nitrogen and creatinine, and proteome changes over the 21-day study period using proteome arrays and bioinformatic methods. At the end of the study period, connective tissue deposition in the kidneys was examined histologically through Sirius Red staining, and the expression of fibrosis- and inflammation-associated genes was determined by reverse transcription quantitative polymerase chain reaction. The blood serum analysis revealed that the transplanted human UdRPC transiently influenced the secretome in mice. Furthermore, the transplanted cells improved renal fibrosis resulting from IRI, indicating therapeutic relevance. Deposition of extracellular matrix proteins and the expression of fibrosis-associated genes, such as connective tissue growth factor as well as collagen 1α2 and 3α1 chains, significantly decreased in the injured kidney after UdRPC transplantation. The expression of genes linked to inflammation and chronic kidney disease, such as monocyte chemoattractant protein 1 and intercellular adhesion molecule 1, was also reduced in mouse kidneys in the presence of UdRPC. K-means cluster analysis of the serum proteome from mice with IRI and transplanted UdRPC at different time points revealed a transient increase in immunomodulatory, antifibrotic, and angiogenic factors that could have triggered these positive effects on acute to chronic mouse kidney disease. Transplanted human UdRPC alleviated the kidney injury severity through ameliorating fibrosis; however, they could not restore complete kidney function within 21 days.

Metastasis is the primary cause of death in advanced/recurrent cancer patients. Cancer metastatic capability depends not only on cancer cells but also on the cancer microenvironment, particularly cancer-associated fibroblasts (CAFs), a highly heterogeneous population. Our prior work identified a POSTN-secreting CAFs subpopulation linked to gastric cancer (GC) invasion and poor survival. The Cancer Genome Atlas analysis in GC showed POSTN association with epithelial-mesenchymal transition and extracellular matrix degradation pathways. In vitro, GC exosomes induced adipose-derived mesenchymal stem cells (MSCs) into POSTN-expressing CAFs. Lentiviral POSTN overexpression in CAFs enhanced GC cell migration/invasion, while knockdown had the opposite effect. These results were validated in a nude mouse GC model. As POSTN is an integrin ligand, POSTN-positive CAFs (POSTN+ CAFs) activated integrin downstream AKT signaling. AKT inhibition significantly diminished the pro-migratory/invasive effect of POSTN-overexpressing CAFs. In summary, POSTN+ CAFs promote GC invasion via AKT pathway activation.

Cannabis use during pregnancy is increasing. In rodent models of delta-9 tetrahydrocannabinol (Δ9-THC) exposure during pregnancy, placental pathology, including compromised labyrinth development, is reported. Cannabinoid receptor 1 (CB1/Cnr1) is the primary mediator of Δ9-THC action, with its expression reportedly limited to the placental junctional zone in the rodent. Given a Δ9-THC-induced labyrinth-specific pathology, we predicted more diverse expression. This study aimed to elucidate the spatiotemporal expression of CB1/Cnr1 in the rodent and assess whether it mediates Δ9-THC-induced alterations in trophoblast differentiation. Results revealed CB1 expression in all maternal blood-facing trophoblast cells. Furthermore, Δ9-THC exposure (at levels matching those reported in maternal serum) had a more significant effect on the expression of markers associated with differentiating trophoblast cells than on proliferating trophoblast stem (TS) cells. Δ9-THC impacted mouse (m) TS cell differentiation in a CB1-dependent manner, reducing the expression of syncytiotrophoblast (SynT) markers, driving differentiation along the junctional zone/trophoblast giant cell pathway. mTS cells without Cnr1/CB1 (mTS^Cnr1KO) did not express markers of SynT cells or the differentiated junctional zone cell types. However, at a higher than physiologically relevant concentration, Δ9-THC (15 μM) induced Gcm1 (SynT) expression in mTS^Cnr1KO cells. This study reveals a mechanism by which Δ9-THC may impact placental growth.

Mesenchymal stromal cells (MSCs) are currently used in clinical practice as a therapeutic agent for immunomodulation and tissue repair. They are found in all supporting tissues, including perinatal tissues such as umbilical cord and amniotic membranes (amnion and chorion). Perinatal tissues have attracted interest due to their availability, minimal ethical and legal concerns, and high banking potential for allogeneic applications. Many studies have compared the efficacy of MSCs from different sources, without reaching a consensus on the most effective to use in a given clinical situation. This study compared the transcriptomic signatures of MSCs derived from adult bone marrow (BM-MSCs)-the reference source most widely used in clinical trials-with those of perinatal MSCs (P-MSCs). Our data were analyzed jointly with three independent transcriptome datasets. Unsupervised principal component analysis revealed a major stratification according to tissue origin, accounting for 16.6% of the total transcriptomic variance, without any detectable bias from batch effects or cell culture procedures. Supervised differential expressed gene analysis between BM and perinatal samples revealed 819 genes presenting differential expression. Gene Set Enrichment Analysis highlighted that adult BM-MSCs are implicated in adipogenesis and osteoblast differentiation, whereas P-MSCs upregulated gene sets implicated in cell cycle regulation, functions classically described in the literature. Among the different sources of variability, we showed that perinatal tissues have a strongly distinct transcriptional signature compared with adult BM, independent of the production center or the culture conditions used. The in-depth study of transcript profiles therefore seems to remain a valuable and robust characterization tool for cell therapy banking.