Regulation Of Stem Cells Research Articles

Heat stress-induced decapping of WUSCHEL mRNA enhances stem cell thermotolerance in Arabidopsis

The plasticity of stem cells in response to environmental change is critical for multicellular organisms. Here, we show that MYB3R-like directly activates the key plant stem cell regulator WUSCHEL (WUS) by recruiting the methyltransferase ROOT INITIATION DEFECTIVE 2 (RID2), which functions in m7G methylation at the 5’ cap of WUS mRNA to protect it from degradation. We demonstrated that protein-folding genes are repressed by WUS to maintain precise protein synthesis in stem cells by preventing the reuse of misfolded proteins. However, upon heat stress, the MYB3R-like/RID2 module is repressed to reduce WUS transcripts via the decapping of nascent WUS mRNA. This releases the inhibition of protein folding capacity in stem cells and protects plant stem cells from heat-shock by eliminating misfolded protein aggregation. Our results reveal a tradeoff strategy in plants by reducing the accuracy of protein synthesis in exchange for the survival of stem cells at high temperatures.

Age-associated imbalance in immune cell regeneration varies across individuals and arises from a distinct subset of stem cells.

The age-associated decline in immunity manifests as imbalanced adaptive and innate immune cells, which originate from the aging of the stem cells that sustain their regeneration. Aging variation across individuals is well recognized, but its mechanism remains unclear. Here, we used high-throughput single-cell technologies to compare mice of the same chronological age that exhibited early or delayed immune aging phenotypes. We found that some hematopoietic stem cells (HSCs) in earlyaging mice upregulated genes related to aging, myeloid differentiation, and stem cell proliferation. Delayed aging was instead associated with genes involved in stem cell regulation and the response to external signals. These molecular changes align with shifts in HSC function. We found that the lineage biases of 30% to 40% of the HSC clones shifted with age. Moreover, their lineage biases shifted in opposite directions in mice exhibiting an early or delayed aging phenotype. In earlyaging mice, the HSC lineage bias shifted toward the myeloid lineage, driving the aging phenotype. In delayedaging mice, HSC lineage bias shifted toward the lymphoid lineage, effectively counteracting aging progression. Furthermore, the anti-aging HSC clones did not increase lymphoid production but instead decreased myeloid production. Additionally, we systematically quantified the frequency of various changes in HSC differentiation and their roles in driving the immune aging phenotype. Taken together, our findings suggest that temporal variation in the aging of immune cell regeneration among individuals primarily arises from differences in the myelopoiesis of a distinct subset of HSCs. Therefore, interventions to delay aging may be possible by targeting a subset of stem cells.

"Osteo-Organogenesis Niche" Hyaluronic Acid Engineered Materials Directing Re-Osteo-Organogenesis via Manipulating Macrophage CD44-MAPK/ERK-ETV1/5-MRC1 Axis.

The strategy of re-organogenesis provides an optimal framework for restoring complex organ structures and functions in adult damage. While the focus has often been on restoring organogenesis stem cells, there is limited investigations of reverting the environmental niche to support this approach. The guiding principle of "Nature selects the fittest to survive" drives the intricate dynamic changes in cellular events within the niche environment, especially through immune surveillance. The extracellular matrix (ECM) serves as the "self-associated molecular patterns" of the niche, containing extensive data on cell-niche reaction data and acting as the active tuner of immune surveillance. In this study, hyaluronic acid (HA) is identified as a unique component of the ECM in cranial osteo-organogenesis. Mechanistically, HA activates the Cluster of Differentiation 44 (CD44)-Mitogen-Activated Protein Kinase (MAPK)/Extracellular Signal-Regulated Kinase (ERK)-Ets Variant 1/5 (ETV1/5)- Mannose Receptor C-Type 1 (MRC1) axis in macrophages, establishing a distinct immune surveillance during osteo-organogenesis. Furthermore, HA is utilized as a novel engineered material for an "Osteo-organogenesis niche", restoring immune surveillance and synergistically regulating stem cells to achieve re-osteo-organogenesis in cranial defects of rats. Taken together, the study unveils a previously unknown strategy for leveraging re-organogenesis by utilizing "organogenesis niche" ECM engineered materials to manipulate immune surveillance, thereby comprehensively regulating stem cells and other tissue cells effectively for re-organogenesis.

Harnessing Ascidians as Model Organisms for Environmental Risk Assessment

Environmental Risk Assessment (ERA) often relies on a restricted set of species as bio-indicators, introducing uncertainty when modeling complex environmental variables. This may lead to oversimplified or erroneous risk assessments. Ascidians, marine filter-feeding sessile chordates, are valuable models for scientific research in various biological fields such as stem cell biology, embryogenesis, regeneration, innate immunity, and developmental biology. Their global distribution, sensitivity to pollutants, high abundance, mass sexual reproduction, and habitation in coastal areas impacted by anthropogenic pollution make them excellent indicators for monitoring marine pollution and global environmental changes, including biological invasions and species diversity diminution cases. Despite their potential as environmental bioindicators, ascidians remain underutilized in ERAs (≤0.13% of ERA studies), particularly in the field of chemical pollution impact assessment, primarily due to a lack of standardization. This underrepresentation poses a challenge for accurate modeling, especially in models relying on a broad range of species (e.g., Species Sensitivity Distributions). Given these constraints, expanding the use of ascidians in ERAs could improve the comprehension and precision of environmental changes and their assessments. This underscores the necessity for future research to establish standardized testing protocols and choose the most suitable ascidian species for inclusion in ERAs.

Role of Sam68 in different types of cancer (Review).

Src‑associated in mitosis 68 kDa protein (Sam68) is a protein encoded by the heteronuclear ribonucleoprotein particle K homology (KH) single domain‑containing, RNA‑binding, signal transduction‑associated protein 1 (known as KHDRBS1) gene in humans. This protein contains binding sites for critical components in a variety of cellular processes, including the regulation of gene expression, RNA processing and cell signaling. Thus, Sam68 may play a role in a variety of diseases, including cancer. Sam68 has been widely demonstrated to participate in tumor cell proliferation, progression and metastasis to be involved in the regulation of cancer stem cell self‑renewal. Based on the body of evidence available, Sam68 emerges as a promising target for this disease. The objectives of the present included summarizing the role of Sam68 in cancer murine models and cancer patients, unraveling the molecular mechanisms underlying its oncogenic potential and discussing the effectiveness of antitumor agents in reducing the malignant effects of Sam68 during tumorigenesis.

SlugAtlas, a histological and 3D online resource of the land slugs Deroceras laeve and Ambigolimax valentianus.

Due to their distinctive anatomical characteristics, land slugs are appealing research subjects from a variety of angles, including stem cell biology, regeneration, embryonic development, allometry, and neurophysiology. Here we present SlugAtlas, an anatomical and histological online resource of the land slugs Deroceras laeve and Ambigolimax valentianus. The atlas is composed of series of histological sections on the horizontal, sagittal, and transversal planes for both species with 3D viewing tools of their major organs. The atlas was used in this work for a comparative analysis of the major organs and tissues of these two species. We provide a comprehensive histological description of them and an explanation of novel findings of unique features of their anatomy. For D. laeve, we additionally studied its ability for degrowth and regrowth, a feature that characterizes animals with high regeneration potential and obtained initial results on the study of the regeneration of its tail. SlugAtlas is a resource that is also built to accommodate future growth and, along with the experimental techniques that we have developed, will provide the foundation for research projects in a variety of biological domains.

Effects of inorganic phosphate on stem cells isolated from human exfoliated deciduous teeth

Calcium phosphate-based materials (CaP) are introduced as potential dental pulp capping materials for deciduous teeth. The present study investigated the influence of inorganic phosphate (Pi) on regulating stem cells isolated from human exfoliated deciduous teeth (SHED). SHEDs were treated with Pi. Cell cycle progression and apoptosis were examined using flow cytometry analysis. Osteo/odontogenic and adipogenic differentiation were analyzed using alizarin red S and oil red O staining, respectively. The mRNA expression profile was investigated using a high-throughput RNA sequencing technique. Pi increased the late apoptotic cell population while cell cycle progression was not altered. Pi upregulated osteo/odontoblastic gene expression and enhanced calcium deposition. Pi-induced mineralization was reversed by pretreatment of cells with Foscarnet, or p38 inhibitor. Pi treatment inhibited adipogenic differentiation as determined by decreased PPARγ expression and reduced intracellular lipid accumulation. Bioinformatic analysis of gene expression profiles demonstrated several involved pathways, including PI3K/AKT, MAPK, EGFR, and VEGF signaling. In conclusion, Pi enhanced osteo/odontogenic but inhibited adipogenic differentiation in SHED.

A Macroscopic Exploration of the Ideoscape on Exosomes for Bone Regeneration

Background: Exosomes, nanoscale extracellular vesicles, play a crucial role in tissue physiology and regeneration. This study uses infometric techniques to explore the structure of exosome-based tissue and bone regeneration research. Methods: We applied BERTopic, an advanced topic modeling algorithm, to a comprehensive corpus of the scientific literature on exosomes and tissue regeneration, identifying key themes such as stem cell studies, tissue healing, and regenerative applications, with orthopedics and dentistry emerging as dominant subfields. To further investigate the ‘ideoscape’, i.e., the conceptual landscape that maps how ideas, methods, and themes are interconnected across the field, we extracted significant concepts from abstracts using GPT 3.5 turbo and created knowledge graphs. Results: Our analysis revealed rapid growth in the field of dental stem cell regeneration, which has outpaced other bone regeneration topics by twofold. This analysis highlighted central themes such as periodontal stem cells and their cellular processes—proliferation, migration, and differentiation—along with their clinical applications. Our approach provided a clear visualization of the field’s intellectual structure, showing how emerging topics are interconnected. Our findings offer a comprehensive view of the evolving trends in exosome-based bone regeneration, revealing not only the most active research areas but also gaps and opportunities for further investigation. Conclusions: This study exemplifies the utility of combining topic modeling with knowledge graph creation to map research trends, offering a flexible and largely automated tool for researchers to explore the vast bodies of literature and guide future research directions.

12408 Efnb2 Controls Pituitary Gland Development By Regulating Proliferation Of Pituitary Stem Cells

Abstract Disclosure: A. Gualtieri: None. L. Gomez-Corral: None. J. Nicholson: None. R. Tan: None. L. Guasti: None. C. Gaston-Massuet: None. Efnb2 encodes for the ligand Ephrinb2 that binds to its cognate Eph receptor, which plays an integral role in angiogenesis, stem cell regulation and tumorigenesis. Using a pituitary-specific Cre-driver (Hesx1Cre), we conditionally deleted Efnb2 from the early pituitary stem/progenitor cells (PSCs) of the developing pituitary gland. We found that Efnb2 is expressed in PSCs both during embryogenesis and adulthood, suggesting its involvement in PSCs maintenance. Here we show that genetic ablation of Efnb2 (Efnb2fl/fl;Hesx1Cre/+) results in severe pituitary hyperplasia, abnormal gland morphogenesis and delay in the terminal differentiation of hormone-producing cells. In order to understand the underlying molecular mechanisms by which Efnb2 deletion leads to pituitary abnormalities during embryogenesis, we performed transcriptomic analyses using mRNA-Seq at early stages of pituitary development on Efnb2+/+ and Efnb2−/− cell populations. Interestingly, unsupervised gene set enrichment analyses of the transcriptomic results identified Efnb2 as a key negative regulator of PSCs proliferation, whilst involved in the regulation of epithelial integrity and epithelial to mesenchymal transition (EMT). Functional assays performed to validate transcriptomic analyses revealed that Efnb2-null PSCs hyper-proliferate both in vitro and in vivo and downregulate the expression of genes involved in EMT, indicating a role of Efnb2 in these two developmental pathways. Indeed, whilst Efnb2-null PSCs within the marginal zone hyper-proliferate, they downregulate genes of epithelial integrity, resulting in an abnormal EMT transcriptomic profile. Additionally, these events lead to a significant delay of the pituitary cell lineage commitment program, leading to severe reduction in the expression of Pit1, Pomc1 and Gsu commitment markers. Taken together, our results reveal a novel role for Efnb2 (Ephrinb2) as key regulator of pituitary gland development. Efnb2 negatively regulates the proliferation of pituitary stem/progenitor cells controlling pituitary organ size while controlling the epithelial integrity of the stem cell niche. Presentation: 6/2/2024

7157 Unveiling PROP1 protein complex: NFIB as a key candidate in pituitary development

Abstract Disclosure: L.C. Iglesias García: None. M.F. Mercogliano: None. C. Schuster: None. L. Cheung: None. F. Brunello: None. V. Michan: None. M. Waldman: None. L. Defelipe: None. M. Martí: None. S.A. Camper: None. M.I. Perez-Millan: None. The transcription factor PROP1 is essential for pituitary development, and mutations in the gene are the most common cause of hypopituitarism in children. To understand PROP1 function, it is essential to identify the protein components of the PROP1 transcription complex. Rapid immunoprecipitation and mass spectrometry (RIME) experiments in GHFT1 cells, genetically engineered to express biotin-tagged PROP1, have revealed the association of PROP1 with 43 transcription factors (including β-CATENIN and the Nuclear Factor I/B). In silico analysis showed association between the armadillo domains of β-CATENIN and a predicted nuclear localization signal motif of PROP1. This interaction between PROP1 and β-CATENIN was confirmed in pituitary GHFT1 cells, where over-expression of PROP1 induces the translocation of β-CATENIN from the membrane and cytoplasm to the nucleus. Moreover, in pituitaries from Prop1df/df mutant embryos at e12.5, β-CATENIN was predominantly membrane-bound compared to wild-type embryos. These findings suggest that PROP1 is necessary for translocation of β-CATENIN to the nucleus during pituitary development.The association of PROP1 with NFIB is intriguing because PROP1 is necessary for the epithelial to mesenchymal-like transition of stem cells in pituitary development, and NFIB is associated with induction of EMT in several cancer models. We used immunohistochemistry to show that NFIB is expressed in embryonic pituitary glands from e12.5 to e16.5, and it co-localizes with the stem cell marker SOX2. To determine whether PROP1 and NFIB have common downstream targets, we performed CUT&RUN experiments for NFIB in GHFT-1 cells and compared the results with those from PROP1 ChIP-seq. Both PROP1 and NFIB bind to three sites in the NFIB gene, suggesting that NFIB is a downstream target of PROP1 and subject to autoregulation. Consistent with this idea, NFIB is reduced in pituitaries from Prop1df/df embryos at both e12.5 and e14.5 relative to normal littermates. Integration of the results from PROP1 ChIP-seq and RNA-seq (GHFT1 vs PROP1-GHFT1 cells) with NFIB CUT&RUN generated a list of 190 potential target genes. These genes are associated with cell migration, emphasizing their correlation with the EMT-like process orchestrated by PROP1 during pituitary development. In sum, we have identified an interesting set of PROP1 interacting proteins, including the transcription factor NFIB, which plays an important role in regulating stem cell differentiation in several organ systems. We have also cataloged the genome-wide set of binding sites for PROP1 and NFIB, which overlap at many genes regulating cell migration, a process that is important for pituitary stem cells to leave the niche and initiate differentiation. Presentation: 6/3/2024

Tuft cells act as regenerative stem cells in the human intestine

In mice, intestinal tuft cells have been described as a long-lived, postmitotic cell type. Two distinct subsets have been identified: tuft-1 and tuft-2 (ref. 1). By combining analysis of primary human intestinal resection material and intestinal organoids, we identify four distinct human tuft cell states, two of which overlap with their murine counterparts. We show that tuft cell development depends on the presence of Wnt ligands, and that tuft cell numbers rapidly increase on interleukin-4 (IL-4) and IL-13 exposure, as reported previously in mice2–4. This occurs through proliferation of pre-existing tuft cells, rather than through increased de novo generation from stem cells. Indeed, proliferative tuft cells occur in vivo both in fetal and in adult human intestine. Single mature proliferating tuft cells can form organoids that contain all intestinal epithelial cell types. Unlike stem and progenitor cells, human tuft cells survive irradiation damage and retain the ability to generate all other epithelial cell types. Accordingly, organoids engineered to lack tuft cells fail to recover from radiation-induced damage. Thus, tuft cells represent a damage-induced reserve intestinal stem cell pool in humans.

The cleavage of WOX5 by the peptidase DA1 connects cytokinin signaling and root stem cell regulation.

The root system of a plant is essential for plant growth and development because it absorbs nutrients and water from the soil. The root stem cells are maintained and replenished by the quiescent center and are essential for the formation of the specific root structure. In Arabidopsis, the WUSCHEL-RELATED HOMEOBOX 5 (WOX5) plays a key role in regulating root stem cell fate. However, which factor can directly modulate the stability of WOX5 protein remains totally unknown. Here, we report that the peptidase DA1 (LARGE IN CHINESE) interacts with and cleaves WOX5, resulting in the destabilization of WOX5. Genetic analyses support that DA1 acts through WOX5 to regulate root stem cell function. We further demonstrate that cytokinin (CK) signaling induces the accumulation of DA1 protein, thereby decreasing the abundance of WOX5 protein in the root. Consistent with these results, the mutation in DA1 increases the layers of columella stem cells and influences CK-induced differentiation of columella stem cells. Thus, our results reveal a previously unrecognized mechanism by which the cleavage of WOX5 by DA1 connects CK signaling and root stem cell function in Arabidopsis.

Cellular stress and epigenetic regulation in adult stem cells.

Stem cells are a unique class of cells that possess the ability to differentiate and self-renew, enabling them to repair and replenish tissues. To protect and maintain the potential of stem cells, the cells and the environment surrounding these cells (stem cell niche) are highly responsive and tightly regulated. However, various stresses can affect the stem cells and their niches. These stresses are both systemic and cellular and can arise from intrinsic or extrinsic factors which would have strong implications on overall aging and certain disease states. Therefore, understanding the breadth of drivers, namely epigenetic alterations, involved in cellular stress is important for the development of interventions aimed at maintaining healthy stem cells and tissue homeostasis. In this review, we summarize published findings of epigenetic responses to replicative, oxidative, mechanical, and inflammatory stress on various types of adult stem cells.

A Novel Human Amniotic Membrane Suspension Improves the Therapeutic Effect of Mesenchymal Stem Cells on Myocardial Infarction in Rats

Mesenchymal stem cell (MSC) therapy aids cardiac repair and regeneration, but the low rate of MSC survival and engulfment in the infarcted heart remains a major obstacle for routine clinical application. Here, an injectable suspension of human acellular amniotic membrane (HAAM) that may serve as synergistic cell delivery vehicle for the treatment of myocardial infarction (MI) by improving MSC homing and survival is developed. The results demonstrate that compared with MSC transplantation alone, HAAM‐loaded MSCs have higher survival and engraftment rates in infarcted tissue, alleviated hypoxia‐induced myocardial damage, achieved higher improvements in cardiac function, promoted angiogenesis, and reduced myocardial fibrosis. In addition, HAAM‐loaded MSCs increase N‐cadherin levels and thereby enhance the efficacy of MSCs in treating MI. This study provides a new approach for MSC‐based cardiac repair and regeneration.

Regenerative stem cell therapy for stroke in Europe (RESSTORE): a multicenter randomized controlled efficacy clinical trial

Regenerative stem cell therapy for stroke in Europe (RESSTORE): a multicenter randomized controlled efficacy clinical trial

The sensory nerve regulates stem cell homeostasis through Wnt5a signaling

The sensory nerve regulates stem cell homeostasis through Wnt5a signaling

Poly (A) binding protein 2 is critical for stem cell differentiation during regeneration in the planarian Schmidtea mediterranea.

Post-transcriptional regulation has emerged as a key mechanism for regulating stem cell renewal and differentiation, which is essential for understanding tissue regeneration and homeostasis. Poly(A)-binding proteins are a family of RNA-binding proteins that play a vital role in post-transcriptional regulation by controlling mRNA stability and protein synthesis. The involvement of poly(A) binding proteins in a wide range of cellular functions is increasingly being investigated. In this study, we used the regenerative model planarian organism Schmidtea mediterranea to demonstrate the critical role of poly(A)-binding protein 2 (PABP2) in regulating neoblast maintenance and differentiation. A deficit in PABP2 blocks the transition of neoblasts toward immediate early progenitors, leading to an enhanced pool of non-committed neoblasts and a decreased progenitor population. This is reflected in variations in the transcriptome profile, providing evidence of downregulation in multiple lineages. Thus, an insufficiency of PABP2 resulted in defective formation and organization of tissue, leading to abnormal regeneration. Our study reveals the essential role of PABP2 in regulating genes that mediate stem cell commitment to early progenitors during tissue regeneration.

Low-energy electric shock ameliorates cell proliferation, morphallaxis, and regeneration via driving key regenerative proteins in earthworm and 3T3 cells

Electric stimulation regulates many cellular processes like cell proliferation, differentiation, apoptosis and cellular migration. Despite its crucial role in regulating stem cells and regeneration, it remains underexplored in both in-vivo and in-vitro settings. In this study, Eudrilus eugeniae are subjected to electric stimulation (1.5 V) prior and after amputation and which augments regeneration up to double-time. Blocking epimorphosis using 2 M thymidine retracts regeneration kinetics to one-third but such inhibition was rescued by applying electric stimulation which propels an overactive morphallaxis pattern of regeneration. Excreting electric stimulation on control worms shows minimal impact, whereas it enhances the key regenerative proteins like VEGF, COX2, YAP, c-Myc, and Wnt3a on amputated worms. Upon blocking epimorphosis, all these key regenerative proteins are down-regulated but through electric stimulation, the cells are reprogrammed to express a triple fold of the mentioned regenerative proteins, that further promotes morphallaxis. In 3T3 cells, electric stimulation accelerates cell proliferation and migrations in 5 secs exposure and it exerts its function by overexpressing VEGF mediated by MEK1. Wnt3a expression was gradually upregulated in increasing exposure (5 and 25 secs) which aids in maintaining the stemness property. The molecular mechanism underlying regeneration capability can assist in designing novel therapeutic applications.

Nanoengineered Endocytic Biomaterials for Stem Cell Therapy

AbstractStem cells, ideal for the tissue repair and regeneration, possess extraordinary capabilities of multidirectional differentiation and self‐renewal. However, the limited spontaneous differentiation potential makes it challenging to harness them for tissue repair without external intervention. Although conventional approaches using biomolecules, small organic molecules, and ions have shown specific and effective functions, they face challenges such as in vivo diffusion and degradation, poor internalization, and side effects on adjacent cells. Nanoengineered biomaterials offer a solution by solidifying and nanosizing these soluble regulating molecules and ions, facilitating their uptake by stem cells. Once inside lysosomes, these nanoparticles release their contents in a controlled “molecule or ion storm,” efficiently altering the intracellular biological and chemical microenvironment to tune the differentiation of stem cells. This newly emerged approach for regulating stem cell fate has attracted much attention in recent years. This method has shown promising results and is poised to enhance clinical stem cell therapy. This review provides an overview of the design principles for nanoengineered biomaterials, discusses the categories and characteristics of nanoparticles, summarizes the application of nanoparticles in tissue repair and regeneration, and discusses the direction of nanoparticle‐enhanced stem cell therapy and prospects for its clinical application in regenerative medicine.

Inflammation-Associated Stem Cells in Gastrointestinal Cancers: Their Utility as Prognostic Biomarkers and Therapeutic Targets.

Stem cells are critical for the development and homeostasis of the gastrointestinal (GI) tract. Inflammatory molecules are known to regulate the activity of stem cells. A comprehensive review specifically describing the role of inflammatory molecules in the regulation of stem cells within the GI tract and in GI cancers (GICs) is not available. This review focuses on understanding the role of inflammatory molecules and stem cells in maintaining homeostasis of the GI tract. We further discuss how inflammatory conditions contribute to the transformation of stem cells into tumor-initiating cells. We also describe the molecular mechanisms of inflammation and stem cell-driven progression and metastasis of GICs. Furthermore, we report on studies describing the prognostic value of cancer stem cells and the clinical trials evaluating their therapeutic utility. This review provides a detailed overview on the role of inflammatory molecules and stem cells in maintaining GI tract homeostasis and their implications for GI-related malignancies.