Regulation Of Stem Cells Research Articles

The Potential Benefits of Fasting Do Not Include Regenerative Stem Cells

Tracing back to the first civilizations, there has always been a drive to live longer healthier lives, to cheat death. As potions and prayers gave way to science, deeper understanding of the body’s chemicals and processes encouraged people to manipulate them in a quest to avoid disease. With the awareness and comprehension of stem cells, new questions arose, many of which were directed at how we might control stem cells that exist throughout the body to our benefit, or how we might utilize them to prevent or manage illness. An increasing number of studies appear to point to the ability of stem cells to regenerate through fasting, which could have potentially far-reaching implications in future approaches towards medical applications. The beneficial effects of fasting – though numerous – do not, however, include stem cell regeneration; instead, it is the cumulative effects of many of our body’s other mechanisms that tend to work together in rejuvenating cells of all types. Further, it is misleading to think that fasting will benefit every person in every situation, as it comes with its own complications and as such, is only recommended in very specific circumstances.

Zinc finger protein 831 promotes apoptosis and enhances chemosensitivity in breast cancer by acting as a novel transcriptional repressor targeting the STAT3/Bcl2 signaling pathway

Emerging evidence suggested that zinc finger protein 831 (ZNF831) was associated with immune activity and stem cell regulation in breast cancer. Whereas, the roles and molecular mechanisms of ZNF831 in oncogenesis remain unclear. ZNF831 expression was significantly diminished in breast cancer which was associated with promoter CpG methylation but not mutation. Ectopic over-expression of ZNF831 suppressed breast cancer cell proliferation and colony formation and promoted apoptosis in vitro, while knockdown of ZNF831 resulted in an opposite phenotype. Anti-proliferation effect of ZNF831 was verified in vivo. Bioinformatic analysis of public databases and transcriptome sequencing both showed that ZNF831 could enhance apoptosis through transcriptional regulation of the JAK/STAT pathway. ChIP and luciferase report assays demonstrated that ZNF831 could directly bind to one specific region of STAT3 promoter and induce the transcriptional inhibition of STAT3. As a result, the attenuation of STAT3 led to a restraint of the transcription of Bcl2 and thus accelerated the apoptotic progression. Augmentation of STAT3 diminished the apoptosis-promoting effect of ZNF831 in breast cancer cell lines. Furthermore, ZNF831 could ameliorate the anti-proliferation effect of capecitabine and gemcitabine in breast cancer cell lines. Our findings demonstrate for the first time that ZNF831 is a novel transcriptional suppressor through inhibiting the expression of STAT3/Bcl2 and promoting the apoptosis process in breast cancer, suggesting ZNF831 as a novel biomarker and potential therapeutic target for breast cancer patients.

Protective effects of activated vitamin D receptor on radiation‐induced intestinal injury

Radiation-induced intestinal injury (RIII) is a common complication after radiation therapy in patients with pelvic, abdominal, or retroperitoneal tumours. Recently, in the model of DSS (Dextran Sulfate Sodium Salt) -induced intestinal inflammatory injury, it has been found in the study that transgenic mice expressing hVDR in IEC (Intestinal Epithelial Cell) manifest highly anti-injury properties in colitis, suggesting that activated VDR in the epithelial cells of intestine may inhibit colitis by protecting the mucosal epithelial barrier. In this study, we investigated the effect of the expression and regulation of VDR on the protection of RIII, and the radiosensitivity in vitro experiments, and explored the initial mechanism of VDR in regulating radiosensitivity of IEC. As a result, we found that the expression of VDR in intestinal tissues and cells in mice can be induced by ionizing radiation. VDR agonists are able to prolong the average survival time of mice after radiation and reduce the radiation-induced intestinal injury. For lack of vitamin D, the radiosensitivity of intestinal epithelial cells in mice increased, which can be reduced by VDR activation. Ensuing VDR activation, the radiation-induced intestinal stem cells damage is decreased, and the regeneration and differentiation of intestinal stem cells is promoted as well. Finally, on the basis of sequencing analysis, we validated and found that VDR may target the HIF/PDK1 pathway to mitigate RIII. We concluded that agonism or upregulation of VDR expression attenuates radiation-induced intestinal damage in mice and promotes the repair of epithelial damage in intestinal stem cells.

Efficient bone regeneration of BMP9-stimulated human periodontal ligament stem cells (hPDLSCs) in decellularized bone matrix (DBM) constructs to model maxillofacial intrabony defect repair

BackgroundBMP9-stimulated DPSCs, SCAPs and PDLSCs are effective candidates for repairing maxillofacial bone defects in tissue engineering, while the most suitable seed cell source among these three hDMSCs and the optimal combination of most suitable type of hDMSCs and BMP9 have rarely been explored. Moreover, the orthotopic maxillofacial bone defect model should be valuable but laborious and time-consuming to evaluate various candidates for bone regeneration. Thus, inspired from the maxillofacial bone defects and the traditional in vivo ectopic systems, we developed an intrabony defect repair model to recapitulate the healing events of orthotopic maxillofacial bone defect repair and further explore the optimized combinations of most suitable hDMSCs and BMP9 for bone defect repair based on this modified ectopic system.MethodsIntrabony defect repair model was developed by using decellularized bone matrix (DBM) constructs prepared from the cancellous part of porcine lumbar vertebral body. We implanted DBM constructs subcutaneously on the flank of each male NU/NU athymic nude mouse, followed by directly injecting the cell suspension of different combinations of hDMSCs and BMP9 into the central hollow area of the constructs 7 days later. Then, the quality of the bony mass, including bone volume fraction (BV/TV), radiographic density (in Hounsfield units (HU)) and the height of newly formed bone, was measured by micro-CT. Furthermore, the H&E staining and immunohistochemical staining were performed to exam new bone and new blood vessel formation in DBM constructs.ResultsBMP9-stimulated periodontal ligament stem cells (PDLSCs) exhibited the most effective bone regeneration among the three types of hDMSCs in DBM constructs. Furthermore, an optimal dose of PDLSCs with a specific extent of BMP9 stimulation was confirmed for efficacious new bone and new blood vessel formation in DBM constructs.ConclusionsThe reported intrabony defect repair model can be used to identify optimized combinations of suitable seed cells and biological factors for bone defect repair and subsequent development of efficacious bone tissue engineering therapies.

Biomaterial application strategies to enhance stem cell-based therapy for ischemic stroke

Ischemic stroke is a condition in which an occluded blood vessel interrupts blood flow to the brain and causes irreversible neuronal cell death. Transplantation of regenerative stem cells has been proposed as a novel therapy to restore damaged neural circuitry after ischemic stroke attack. However, limitations such as low cell survival rates after transplantation remain significant challenges to stem cell-based therapy for ischemic stroke in the clinical setting. In order to enhance the therapeutic efficacy of transplanted stem cells, several biomaterials have been developed to provide a supportable cellular microenvironment or functional modification on the stem cells to optimize their reparative roles in injured tissues or organs. To discuss state-of-the-art functional biomaterials that could enhance the therapeutic potential of stem cell-based treatment for ischemic stroke and provide detailed insights into the mechanisms underlying these biomaterial approaches. The PubMed, Science Direct and Scopus literature databases were searched using the keywords of "biomaterial" and "ischemic stroke". All topically-relevant articles were then screened to identify those with focused relevance to in vivo, in vitro and clinical studies related to "stem cells" OR "progenitor cells" OR "undifferentiated cells" published in English during the years of 2011 to 2022. The systematic search was conducted up to September 30, 2022. A total of 19 articles matched all the inclusion criteria. The data contained within this collection of papers comprehensively represented 19 types of biomaterials applied on seven different types of stem/progenitor cells, namely mesenchymal stem cells, neural stem cells, induced pluripotent stem cells, neural progenitor cells, endothelial progenitor cells, neuroepithelial progenitor cells, and neuroblasts. The potential major benefits gained from the application of biomaterials in stem cell-based therapy were noted as induction of structural and functional modifications, increased stem cell retention rate in the hostile ischemic microenvironment, and promoting the secretion of important cytokines for reparative mechanisms. Biomaterials have a relatively high potential for enhancing stem cell therapy. Nonetheless, there is a scarcity of evidence from human clinical studies for the efficacy of this bioengineered cell therapy, highlighting that it is still too early to draw a definitive conclusion on efficacy and safety for patient usage. Future in-depth clinical investigations are necessary to realize translation of this therapy into a more conscientious and judicious evidence-based therapy for clinical application.

Interleukin-6 is dispensable in pituitary normal development and homeostasis but needed for pituitary stem cell activation following local injury.

Recently, we discovered that the cytokine interleukin-6 (IL-6) acts as a pituitary stem cell-activating factor, both when administered in vivo and when added to stem cell organoid cultures in vitro. Moreover, its expression, predominantly localized in the gland's stem and mesenchymal cells, promptly increases following damage in the adult pituitary, leading to stem-cell proliferative activation. Given these findings that IL-6 is involved in pituitary stem cell regulation, we addressed the question whether the cytokine has an impact on the pituitary phenotype during active phases of the gland's remodeling, in particular embryonic development and neonatal maturation, as well as during homeostasis at adulthood and aging, all unknown today. Using the IL-6 knock-out (KO) mouse model, we show that IL-6 is dispensable for pituitary embryonic and neonatal endocrine cell development, as well as for hormonal cell homeostasis in adult and aging glands. The findings match the absence of effects on the stem cell compartment at these stages. However, using this IL-6 KO model, we found that IL-6 is needed for the acute stem-cell proliferative activation reaction upon pituitary injury. Intriguingly, regeneration still occurs which may be due to compensatory behavior by other cytokines which are upregulated in the damaged IL-6 KO pituitary, although at lower but prolonged levels, which might lead to a delayed (and less forceful) stem cell response. Taken together, our study revealed that IL-6 is dispensable for normal pituitary development and homeostasis but plays a key role in the prompt stem cell activation upon local damage, although its presence is not essentially needed for the final regenerative realization.

Biomimetic Prussian blue nanozymes with enhanced bone marrow-targeting for treatment of radiation-induced hematopoietic injury

There is an urgent medical need to develop effective therapies that can ameliorate damage to the radiation-exposed hematopoietic system. Nanozymes with robust antioxidant properties have a therapeutic potential for mitigating radiation-induced hematopoietic injury. However, enhancing nanozyme recruitment to injured tissues in vivo while maintaining their catalytic activity remains a great challenge. Herein, we present the design and preparation of a biomimetic nanoparticle, a mesenchymal stem cell membrane camouflaged Prussian blue nanozyme (PB@MSCM), which exhibits biocompatible surface properties and demonstrates enhanced injury site-targeting towards the irradiated murine bone marrow niche. Notably, the constructed PB@MSCM possessed redox enzyme-mimic catalytic activity and could scavenge overproduced reactive oxygen species in the irradiated bone marrow cells, both in vitro and ex vivo. More importantly, the administration of PB@MSCM significantly mitigated hematopoietic cell apoptosis and accelerated the regeneration of hematopoietic stem and progenitor cells. Our findings provide a new targeted strategy to improve nanozyme therapy in vivo and mitigate radiation-induced hematopoietic injury.

Single-cell transcriptome reveals core cell populations and androgen-RXFP2 axis involved in deer antler full regeneration

Deer antlers constitute a unique mammalian model for the study of both organ formation in postnatal life and annual full regeneration. Previous studies revealed that these events are achieved through the proliferation and differentiation of antlerogenic periosteum (AP) cells and pedicle periosteum (PP) cells, respectively. As the cells resident in the AP and the PP possess stem cell attributes, both antler generation and regeneration are stem cell-based processes. However, the cell composition of each tissue type and molecular events underlying antler development remain poorly characterized. Here, we took the approach of single-cell RNA sequencing (scRNA-Seq) and identified eight cell types (mainly THY1+ cells, progenitor cells, and osteochondroblasts) and three core subclusters of the THY1+ cells (SC2, SC3, and SC4). Endothelial and mural cells each are heterogeneous at transcriptional level. It was the proliferation of progenitor, mural, and endothelial cells in the activated antler-lineage-specific tissues that drove the rapid formation of the antler. We detected the differences in the initial differentiation process between antler generation and regeneration using pseudotime trajectory analysis. These may be due to the difference in the degree of stemness of the AP-THY1+ and PP-THY1+ cells. We further found that androgen-RXFP2 axis may be involved in triggering initial antler full regeneration. Fully deciphering the cell composition for these antler tissue types will open up new avenues for elucidating the mechanism underlying antler full renewal in specific and regenerative medicine in general.

Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration

Tissue regeneration requires coordination between resident stem cells and local niche cells1,2. Here we identify that senescent cells are integral components of the skeletal muscle regenerative niche that repress regeneration at all stages of life. The technical limitation of senescent-cell scarcity3 was overcome by combining single-cell transcriptomics and a senescent-cell enrichment sorting protocol. We identified and isolated different senescent cell types from damaged muscles of young and old mice. Deeper transcriptome, chromatin and pathway analyses revealed conservation of cell identity traits as well as two universal senescence hallmarks (inflammation and fibrosis) across cell type, regeneration time and ageing. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing (inflammageing4) and arrests stem cell proliferation and regeneration. Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice. By contrast, transplantation of senescent cells delays regeneration. Our results provide a technique for isolating in vivo senescent cells, define a senescence blueprint for muscle, and uncover unproductive functional interactions between senescent cells and stem cells in regenerative niches that can be overcome. As senescent cells also accumulate in human muscles, our findings open potential paths for improving muscle repair throughout life.

MITOCHONDRIAL COMMUNICATION AND AGING

Abstract Mitochondria evidently originate from endosymbiotic bacteria that presumably provided several advantages for eukaryotic life. For the past 1–2 billion years, mitochondria co-evolved with the ancestral cell to coordinate various cellular functions. Coordination requires communication and mitochondrial signaling has been shown to be vital to cellular fitness and aging. In this symposium, the speakers will discuss the role of mitochondria as a signaling organelle and their impact on key cellular functions in the context of aging. Consistent with emerging evidence of the complexity and sophistication of mitochondrial communication mechanisms, some of the mitochondrial-to-nuclear communication modes, including nuclear transcriptional programs and cellular signaling networks, that regulate molecular and cellular processes to promote fitness will be discussed. Dr. Chen will discuss how a mitochondrial metabolic checkpoint can regulate stem cell quiescence and maintenance that is important to stem cell aging. Dr. Picard will discuss the impact of mitochondrial stress on increased energetic cost of living (i.e. hypermetabolism) and cellular lifespan. Finally, Dr. Lee will discuss how signaling peptides that are encoded withing the mitochondrial genome regulate cellular homeostasis, increase physiological resilience, and promote healthy aging.

Notch signaling sculpts the stem cell niche.

Adult stem cells depend on their niches for regulatory signaling that controls their maintenance, division, and their progeny differentiation. While communication between various types of stem cells and their niches is becoming clearer, the process of stem cell niche establishment is still not very well understood. Model genetic organisms provide simplified systems to address various complex questions, for example, how is a stem cell niche formed? What signaling cascades induce the stem cell niche formation? Are the mechanisms of stem cell niche formation conserved? Notch signaling is an evolutionarily conserved pathway first identified in fruit flies, crucial in fate acquisition and spatiotemporal patterning. While the core logic behind its activity is fairly simple and requires direct cell-cell interaction, it reaches an astonishing complexity and versatility by combining its different modes of action. Subtleties such as equivalency between communicating cells, their physical distance, receptor and ligand processing, and endocytosis can have an effect on the way the events unfold, and this review explores some important general mechanisms of action, later on focusing on its involvement in stem cell niche formation. First, looking at invertebrates, we will examine how Notch signaling induces the formation of germline stem cell niche in male and female Drosophila. In the developing testis, a group of somatic gonadal precursor cells receive Delta signals from the gut, activating Notch signaling and sealing their fate as niche cells even before larval hatching. Meanwhile, the ovarian germline stem cell niche is built later during late larval stages and requires a two-step process that involves terminal filament formation and cap cell specification. Intriguingly, double security mechanisms of Notch signaling activation coordinated by the soma or the germline control both steps to ensure the robustness of niche assembly. Second, in the vast domains of mammalian cellular signaling, there is an emerging picture of Notch being an active player in a variety of tissues in health and disease. Notch involvement has been shown in stem cell niche establishment in multiple organs, including the brain, muscle, and intestine, where the stem cell niches are essential for the maintenance of adult stem cells. But adult stem cells are not the only cells looking for a home. Cancer stem cells use Notch signaling at specific stages to gain an advantage over endogenous tissue and overpower it, at the same time acquiring migratory and invasive abilities to claim new tissues (e.g., bone) as their territory. Moreover, in vitro models such as organoids reveal similar Notch employment when it comes to the developing stem cell niches. Therefore, a better understanding of the processes regulating stem cell niche assembly is key for the fields of stem cell biology and regenerative medicines.

Functionalized Nanoparticles: A Paradigm Shift in Regenerative Endodontic Procedures.

Clinical treatment of inflamed tooth pulp mostly involves the removal of the entire pulp tissue. Because the vitality of the tooth is important for its ability to function, optimal regenerative biomaterials must be developed to maintain the vitality. Despite vast advances in the field of endodontics, the clinical translation of regenerative endodontic procedures and materials remains challenging. Patient-specific, tissue-derived stem cells play a major role in regeneration and revascularization, and these stem cells require an infection-free environment for a successful outcome. However, the high doses of antibiotics currently used to maintain an infection-free environment for tissue regeneration can be toxic for the stem cells. The introduction of nanotechnology in the field of regenerative procedures has overcome these issues and demonstrated promising results. Nanoparticles can be used to deliver antibiotics at very low doses owing to their small size, thereby enhancing antimicrobial activity and reducing the cytotoxic effect. Additionally, nanofibrous scaffolds provide an environment that is favorable for stem-cell migration and proliferation, thereby favoring the regeneration of the pulp-dentin complex. Nanotechnology can be used in the construction of nanofibrous scaffolds incorporated with different bioactive nanoparticles for favorable clinical outcomes. Nonetheless, the role of nanotechnology and the controlled release of various bioactive nanomolecules enhancing stem cell proliferation and regeneration of true pulp-dentin complex remains poorly understood. Given the importance of nanotechnology in tissue regeneration, this review provides an overview of the potential applications of nanotechnology in tooth pulp-dentin regeneration.

A Human Bone Marrow 3D Model to Investigate the Dynamics and Interactions Between Resident Cells in Physiological or Tumoral Contexts.

The medullary niche is a complex ecosystem that is essential to maintain homeostasis for resident cells. Indeed, the bone marrow, which includes a complex extracellular matrix and various cell types, such as mesenchymal stem cells, osteoblasts, and endothelial cells, is deeply involved in hematopoietic stem cell regulation through direct cell-cell interactions, as well as cytokine production. To closely mimic this in vivo structure and conduct experiments reflecting the responses of the human bone marrow, several 3D models have been created based on biomaterials, relying primarily on primary stromal cells. Here, a protocol is described to obtain a minimal and standardized system that is easy to set up and provides features of bone marrow-like structure, which combines different cell populations including endothelial cells, and reflects the heterogeneity of in vivo bone marrow tissue. This 3D bone marrow-like structure-assembled using calcium phosphate-based particles and human cell lines, representative of the bone marrow microenvironment-allows the monitoring of a wide variety of biological processes by combining or replacing different primary cell populations within the system. The final 3D structures can then either be harvested for image analysis after fixation, paraffin-embedding, and histological/immunohistochemical staining for cell localization within the system, or dissociated to collect each cellular component for molecular or functional characterization.

Bacteroides fragilis strain ZY-312 promotes intestinal barrier integrity via upregulating the STAT3 pathway in a radiation-induced intestinal injury mouse model.

Radiation-induced intestinal injury is characterized by intestinal barrier impairment. However, the therapeutic effects of probiotics for intestinal epithelial barrier repair in a mouse model of radiation-induced intestinal injury remain unclear. Previously, we isolated a strain of Bacteroides fragilis from the feces of a healthy infant and named it as B. fragilis strain ZY-312 (B. fragilis). In this study, we showed that B. fragilis can ameliorate radiation-induced intestinal injury in mice, manifested by decreased weight loss, intestinal length shortening, and intestinal epithelial cell (IEC) shedding. Moreover, we found that B. fragilis promoted IEC proliferation, stem cell regeneration, mucus secretion, and tight junction integrity by upregulating the STAT3 signaling pathway, through an experimental verification in Stat3 △IEC mice (STAT3 defects in intestinal epithelial cells). Thus, the underlying protective mechanism of B. fragilis in radiation-induced intestinal injury is related to IEC proliferation, stem cell regeneration, goblet cell secretion, and tight junction repair via activation of the STAT3 signaling pathway. In addition, the therapeutic effects of B. fragilis were studied to provide new insights into its application as a functional and clinical drug for radiation-induced intestinal injury after radiotherapy.

A genetic disorder reveals a hematopoietic stem cell regulatory network co-opted in leukemia

The molecular regulation of human hematopoietic stem cell (HSC) maintenance is therapeutically important, but limitations in experimental systems and interspecies variation have constrained our knowledge of this process. Here, we have studied a rare genetic disorder due to MECOM haploinsufficiency, characterized by an early-onset absence of HSCs in vivo. By generating a faithful model of this disorder in primary human HSCs and coupling functional studies with integrative single-cell genomic analyses, we uncover a key transcriptional network involving hundreds of genes that is required for HSC maintenance. Through our analyses, we nominate cooperating transcriptional regulators and identify how MECOM prevents the CTCF-dependent genome reorganization that occurs as HSCs differentiate. We show that this transcriptional network is co-opted in high-risk leukemias, thereby enabling these cancers to acquire stem cell properties. Collectively, we illuminate a regulatory network necessary for HSC self-renewal through the study of a rare experiment of nature.

Transfer RNA-derived small RNAs (tsRNAs) sequencing revealed a differential expression landscape of tsRNAs between glioblastoma and low-grade glioma

BackgroundGlioblastomas (GBMs) are the most lethal brain cancer with a median survival rate of fewer than 15 months. Both clinical and biological features of GBMs are largely different from those of low-grade gliomas (LGs), but the reasons for this intratumoral heterogeneity are not entirely clear. Transfer RNA (tRNA)-derived small RNAs (tsRNAs) were derived from tRNA precursors and mature tRNA, referring to the specific cleavage of tRNAs by dicer and angiogenin (ANG) in particular cells or tissues or under certain conditions such as stress and hypoxia. With the characteristics of wide expression and high stability, tsRNAs could be used as favorable biomarkers for diagnosis, treatment, and prognosis prediction of the tumor, viral infection, neurological as well as other systemic diseases. In this study, we have compared the differential expressed tsRNAs between GBMs and LGs, so as to investigate the possible pathogenic molecules and provide references for discovering novel nucleic acid drugs in future studies. MethodsFresh tumor tissues of patients that were diagnosed as GBMs (4 cases) and LGs (5 cases) at the First Affiliated Hospital of Wenzhou Medical University from 2019.05 to 2021.01 were collected. The tsRNAs’ levels were analyzed and compared through high-throughput sequencing, candidate tsRNAs were chosen according to the expression level, and the expression of the candidate tsRNAs was validated through qPCR. Finally, the potential targets were imputed using the Miranda and TargetScan databases, and possible biological functions of the differentially expressed (DE) tsRNAs' targets were enriched based on GO and KEGG databases. ResultsA total of 4 GBMs and 5 LGs patients were enrolled in the current study. High-throughput sequencing showed that 186 tsRNAs were expressed in two groups, over them, 43 tsRNAs were unique to GBMs, and 24 tsRNAs were unique to LGs. A total of 9 tsRNAs were selected as candidate tsRNAs according to the tsRNA expression level, among which 6 tsRNAs were highly expressed in GBMs and 3 tsRNAs were low expressed in GBMs. qPCR verification further demonstrated that 5 tsRNAs were significantly up-regulated and 1 tsRNA was significantly down-regulated in GBMs: tRF-1-32-chrM.Lys-TTT (p=0.00118), tiRNA-1-33-Gly-GCC-1 (p=0.00203), tiRNA-1-33-Gly-CCC-1 (p=0.00460), tRF-1-31-His-GTG-1 (p=0.00819), tiRNA-1-33-Gly-GCC-2-M3 (p=0.01032), and tiRNA-1-34-Lys-CTT-1-M2 (p=0.03569). Enrichment analysis of the qPCR verified DE tsRNAs showed that the 5 up-regulated tsRNAs seemed to be associated with axon guidance, pluripotent stem cells regulation, nucleotide excision repair, Hippo signaling pathway, and cancer-related pathways, while the down-regulated tsRNA (tRF-1-32-chrM.Lys-TTT) was associated with oocyte meiosis and renin secretion. ConclusionThe tsRNAs were differentially expressed in tumor tissues between GBMs and LGs, especially tRF-1-32-chrM.Lys-TTT, tiRNA-1-33-Gly-GCC-1, tiRNA-1-33-Gly-CCC-1, tRF-1-31-His-GTG-1, tiRNA-1-33-Gly-GCC-2-M3, and tiRNA-1-34-Lys-CTT-1-M2. These tsRNAs seemed to be associated with nucleotide excision repair, Hippo signaling, and cancer-related pathways. This may be the main reason for the differences in clinical characteristics between GBMs and LGs, which may provide a certain theoretical basis for further functional research and development of related nucleic acid drugs.

Mitochondrial Transfer Regulates Cell Fate Through Metabolic Remodeling in Osteoporosis.

Mitochondria are the powerhouse of eukaryotic cells, which regulate cell metabolism and differentiation. Recently, mitochondrial transfer between cells has been shown to direct recipient cell fate. However, it is unclear whether mitochondria can translocate to stem cells and whether this transfer alters stem cell fate. Here, mesenchymal stem cell (MSC) regulation is examined by macrophages in the bone marrow environment. It is found that macrophages promote osteogenic differentiation of MSCs by delivering mitochondria to MSCs. However, under osteoporotic conditions, macrophages with altered phenotypes, and metabolic statuses release oxidatively damaged mitochondria. Increased mitochondrial transfer of M1-like macrophages to MSCs triggers a reactive oxygen species burst, which leads to metabolic remodeling. It is showed that abnormal metabolism in MSCs is caused by the abnormal succinate accumulation, which is a key factor in abnormal osteogenic differentiation. These results reveal that mitochondrial transfer from macrophages to MSCs allows metabolic crosstalk to regulate bone homeostasis. This mechanism identifies a potential target for the treatment of osteoporosis.

Myeloid cells promote interferon signaling-associated deterioration of the hematopoietic system.

Innate and adaptive immune cells participate in the homeostatic regulation of hematopoietic stem cells (HSCs). Here, we interrogate the contribution of myeloid cells, the most abundant cell type in the mammalian bone marrow, in a clinically relevant mouse model of neutropenia. Long-term genetic depletion of neutrophils and eosinophils results in activation of multipotent progenitors but preservation of HSCs. Depletion of myeloid cells abrogates HSC expansion, loss of serial repopulation and lymphoid reconstitution capacity and remodeling of HSC niches, features previously associated with hematopoietic aging. This is associated with mitigation of interferon signaling in both HSCs and their niches via reduction of NK cell number and activation. These data implicate myeloid cells in the functional decline of hematopoiesis, associated with activation of interferon signaling via a putative neutrophil-NK cell axis. Innate immunity may thus come at the cost of system deterioration through enhanced chronic inflammatory signaling to stem cells and their niches.

Cellular and metabolic characteristics of pre-leukemic hematopoietic progenitors with GATA2 haploinsufficiency.

Mono-allelic germline disruptions of the transcription factor GATA2 result in a propensity for developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), affecting more than 85% of carriers. How a partial loss of GATA2 functionality enables leukemic transformation years later is unclear. This question has remained unsolved mainly due to the lack of informative models, as Gata2 heterozygote mice do not develop hematologic malignancies. Here we show that two different germline Gata2 mutations (TgErg/Gata2het and TgErg/Gata2L359V) accelerate AML in mice expressing the human hematopoietic stem cell regulator ERG. Analysis of Erg/Gata2het fetal liver and bone marrow-derived hematopoietic cells revealed a distinct pre-leukemic phenotype. This was characterized by enhanced transition from stem to progenitor state, increased proliferation, and a striking mitochondrial phenotype, consisting of highly expressed oxidative-phosphorylation-related gene sets, elevated oxygen consumption rates, and notably, markedly distorted mitochondrial morphology. Importantly, the same mitochondrial gene-expression signature was observed in human AML harboring GATA2 aberrations. Similar to the observations in mice, non-leukemic bone marrows from children with germline GATA2 mutation demonstrated marked mitochondrial abnormalities. Thus, we observed the tumor suppressive effects of GATA2 in two germline Gata2 genetic mouse models. As oncogenic mutations often accumulate with age, GATA2 deficiency-mediated priming of hematopoietic cells for oncogenic transformation may explain the earlier occurrence of MDS/AML in patients with GATA2 germline mutation. The mitochondrial phenotype is a potential therapeutic opportunity for the prevention of leukemic transformation in these patients.

Targeting redox regulation and autophagy systems in cancer stem cells.

Cancer is a dysregulated cellular level pathological condition that results in tumor formation followed by metastasis. In the heterogeneous tumor architecture, cancer stem cells (CSCs) are essential to push forward the progression of tumors due to their strong pro-tumor properties such as stemness, self-renewal, plasticity, metastasis, and being poorly responsive to radiotherapy and chemotherapeutic agents. Cancer stem cells have the ability to withstand various stress pressures by modulating transcriptional and translational mechanisms, and adaptable metabolic changes. Owing to CSCs heterogeneity and plasticity, these cells display varied metabolic and redox profiles across different types of cancers. It has been established that there is a disparity in the levels of Reactive Oxygen Species (ROS) generated in CSCs vs Non-CSC and these differential levels are detected across different tumors. CSCs have unique metabolic demands and are known to change plasticity during metastasis by passing through the interchangeable epithelial and mesenchymal-like phenotypes. During the metastatic process, tumor cells undergo epithelial to mesenchymal transition (EMT) thus attaining invasive properties while leaving the primary tumor site, similarly during the course of circulation and extravasation at a distant organ, these cells regain their epithelial characteristics through Mesenchymal to Epithelial Transition (MET) to initiate micrometastasis. It has been evidenced that levels of Reactive Oxygen Species (ROS) and associated metabolic activities vary between the epithelial and mesenchymal states of CSCs. Similarly, the levels of oxidative and metabolic states were observed to get altered in CSCs post-drug treatments. As oxidative and metabolic changes guide the onset of autophagy in cells, its role in self-renewal, quiescence, proliferation and response to drug treatment is well established. This review will highlight the molecular mechanisms useful for expanding therapeutic strategies based on modulating redox regulation and autophagy activation to targets. Specifically, we will account for the mounting data that focus on the role of ROS generated by different metabolic pathways and autophagy regulation in eradicating stem-like cells hereafter referred to as cancer stem cells (CSCs).