Differentiation最新文献

Fibroblast Growth Factor 6 (FGF6), also referred to as HST2 or HBGF6, is a member of the Fibroblast Growth Factor (FGF), the Heparin Binding Growth Factor (HBGF) and the Heparin Binding Secretory Transforming Gene (HST) families. The genomic and protein structure of FGF6 is highly conserved among varied species, as is its expression in muscle and muscle progenitor cells. Like other members of the FGF family, FGF6 regulates cell proliferation, differentiation, and migration. Specifically, it plays key roles in myogenesis and muscular regeneration, angiogenesis, along with iron transport and lipid metabolism. Similar to others from the FGF family, FGF6 also possesses oncogenic transforming activity, and as such is implicated in a variety of cancers.

The acquisition of the post-mitotic state is crucial for the execution of many terminally differentiated cell behaviors during organismal development. However, the mechanisms that maintain the post-mitotic state in this context remain poorly understood. To gain insight into these mechanisms, we used the genetically and visually accessible model of C. elegans anchor cell (AC) invasion into the vulval epithelium. The AC is a terminally differentiated uterine cell that normally exits the cell cycle and enters a post-mitotic state before initiating contact between the uterus and vulva through a cell invasion event. Here, we set out to identify the set of negative cell cycle regulators that maintain the AC in this post-mitotic, invasive state. Our findings revealed a critical role for CKI-1 (p21^CIP1/p27^KIP1) in redundantly maintaining the post-mitotic state of the AC, as loss of CKI-1 in combination with other negative cell cycle regulators—including CKI-2 (p21^CIP1/p27^KIP1), LIN-35 (pRb/p107/p130), FZR-1 (Cdh1/Hct1), and LIN-23 (β-TrCP)—resulted in proliferating ACs. Remarkably, time-lapse imaging revealed that these ACs retain their ability to invade. Upon examination of a node in the gene regulatory network controlling AC invasion, we determined that proliferating, invasive ACs do so by maintaining aspects of pro-invasive gene expression. We therefore report that the requirement for a post-mitotic state for invasive cell behavior can be bypassed following direct cell cycle perturbation.

Collagen is a highly abundant protein in the extracellular matrix of humans and mammals, and it plays a critical role in maintaining the body's structural integrity. Type I collagen is the most prevalent collagen type and is essential for the structural integrity of various tissues. It is present in nearly all connective tissues and is the main constituent of the interstitial matrix. Mutations that affect collagen fiber formation, structure, and function can result in various bone pathologies, underscoring the significance of collagen in sustaining healthy bone tissue. Studies on type 1 collagen have revealed that mutations in its encoding gene can lead to diverse bone diseases, such as osteogenesis imperfecta, a disorder characterized by fragile bones that are susceptible to fractures. Knowledge of collagen's molecular structure, synthesis, assembly, and breakdown is vital for comprehending embryonic and foetal development and several aspects of human physiology. In this review, we summarize the structure, molecular biology of type 1 collagen, its biomineralization and pathologies affecting bone.

Heart failure has become a major life-threatening cause affecting millions globally, characterized by the permanent loss of adult functional cardiomyocytes leading to fibrosis which ultimately deprives the heart of its functional efficacy. Here we investigated the reparative property of embryonic and adult epicardial cells towards cardiomyocyte differentiation under oxidative stress-induced conditions along with the identification of a possible molecular signaling pathway. Isolated epicardial cells from embryonic chick hearts subjected to oxidative stress and hypoxia induction. Initial assessment of successful injury induction reveals hypertrophy of isolated epicardial cells. Detailed marker gene expression analyses and inhibitor studies reveal Bone morphogenic protein (Bmp)2-Smad1/5/8 signaling dependent cardiomyocyte lineage specification via epithelial to mesenchymal transition (EMT) post-injury. EMT is further confirmed by increased proliferation, migration, and differentiation towards cardiomyocyte lineage. We have also established an in-vivo model in adult male rats using Isoproterenol. Successful oxidative stress-mediated injury induction in adult heart was marked by increased activated fibroblasts followed by apoptosis of adult cardiomyocytes. The detailed characterization of adult epicardial cells reveals similar findings to our avian in-vitro data. Both in-vitro and in-vivo results show a significant increase in the expression of cardiomyocyte specific markers indicative of lineage specificity and activation of epicardial cells post oxidative stress mediated injury. Our findings suggest an EMT-induced reactivation of epicardial cells and early cardiomyocyte lineage specification following oxidative stress in a Bmp2- Smad1/5/8 dependent manner. Overall, this regulatory mechanism of cardiomyocyte differentiation induced by oxidative stress may contribute to the field of cardiac repair and regenerative therapeutics.

Genetic manipulation in mammals has progressed rapidly in the past decade with the advent of CRISPR-Cas gene editing tools, promising profound impacts on the understanding of human development, health and disease. However, many years of research in divergent fields of experimental embryology, genetics, reproduction, molecular biology and transgenic technology laid the groundwork and have played critical roles for this progress. This article details various threads of research and the central role of the laboratory mouse that came together in reaching this point, all from the perspective of a scientist whose research was deeply immersed in the field.

Epigenetic regulation is a critical component of lineage determination. Adipogenesis is the process through which uncommitted stem cells or adipogenic precursor cells differentiate into adipocytes, the most abundant cell type of the adipose tissue. Studies examining chromatin modification during adipogenesis have provided further understanding of the molecular blueprint that controls the onset of adipogenic differentiation. Unlike histone acetylation, histone methylation has context dependent effects on the activity of a transcribed region of DNA, with individual or combined marks on different histone residues providing distinct signals for gene expression. Over half of the 42 histone methyltransferases identified in mammalian cells have been investigated in their role during adipogenesis, but across the large body of literature available, there is a lack of clarity over potential correlations or emerging patterns among the different players. In this review, we will summarize important findings from studies published in the past 15 years that have investigated the role of histone methyltransferases during adipogenesis, including both protein arginine methyltransferases (PRMTs) and lysine methyltransferases (KMTs). We further reveal that PRMT1/4/5, H3K4 KMTs (MLL1, MLL3, MLL4, SMYD2 and SET7/9) and H3K27 KMTs (EZH2) all play positive roles during adipogenesis, while PRMT6/7 and H3K9 KMTs (G9a, SUV39H1, SUV39H2, and SETDB1) play negative roles during adipogenesis.

Bardet-Biedl syndrome (BBS) is an inherited disorder primarily ciliopathy with pleiotropic multi-systemic phenotypic involvement, including adipose, nerve, retinal, kidney, Etc. Consequently, it is characterized by obesity, cognitive impairment and retinal, kidney and cutaneous abnormalities. Initial studies, including ours have shown that BBS genes play a role in the early developmental stages of adipocytes and β-cells. However, this role in other BBS-related tissues is unknown.

We investigated BBS genes involvement in the proliferation and early differentiation of different BBS cell types.

The involvement of BBS genes in cellular proliferation were studied in seven in-vitro and transgenic cell models; keratinocytes (hHaCaT) and Ras-transfected keratinocytes (Ras-hHaCaT), neuronal cell lines (hSH-SY5Y and rPC-12), silenced BBS4 neural cell lines (siBbs4 hSH-SY5Y and siBbs4 rPC-12), adipocytes (m3T3L1), and ex-vivo transformed B-cells obtain from BBS4 patients, using molecular and biochemical methodologies.

RashHaCaT cells showed an accelerated proliferation rate in parallel to significant reduction in the transcript levels of BBS1, 2, and 4. BBS1, 2, and 4 transcripts linked with hHaCaT cell cycle arrest (G1 phase) using both chemical (CDK4 inhibitor) and serum deprivation methodologies. Adipocyte (m3T3-L1) Bbs1, 2 and 4 transcript levels corresponded to the cell cycle phase (CDK4 inhibitor and serum deprivation). SiBBS4 hSH-SY5Y cells exhibited early cell proliferation and differentiation (wound healing assay) rates. SiBbs4 rPC-12 models exhibited significant proliferation and differentiation rate corresponding to Nestin expression levels. BBS4 patients-transformed B-cells exhibited an accelerated proliferation rate (LPS-induced methodology).

In conclusions, the BBS4 gene plays a significant, similar and global role in the cellular proliferation of various BBS related tissues. These results highlight the universal role of the BBS gene in the cell cycle, and further deepen the knowledge of the mechanisms underlying the development of BBS.

The fovea centralis (fovea) is a specialized region of the primate retina that plays crucial roles in high-resolution visual acuity and color perception. The fovea is characterized by a high density of cone photoreceptors and no rods, and unique anatomical properties that contribute to its remarkable visual capabilities. Early histological analyses identified some of the key events that contribute to foveal development, but the mechanisms that direct the specification of this area are not understood. Recently, the expression of the retinoic acid-metabolizing enzyme CYP26A1 has become a hallmark of some of the retinal specializations found in vertebrates, including the primate fovea and the high-acuity area in avian species. In chickens, the retinoic acid pathway regulates the expression of FGF8 to then direct the development of a rod-free area. Similarly, high levels of CYP26A1, CDKN1A, and NPVF expression have been observed in the primate macula using transcriptomic approaches. However, which retinal cells express these genes and their expression dynamics in the developing primate eye remain unknown. Here, we systematically characterize the expression patterns of CYP26A1, FGF8, CDKN1A, and NPVF during the development of the rhesus monkey retina, from early stages of development in the first trimester until the third trimester (near term). Our data suggest that some of the markers previously proposed to be fovea-specific are not enriched in the progenitors of the rhesus monkey fovea. In contrast, CYP26A1 is expressed at high levels in the progenitors of the fovea, while it localizes in a subpopulation of macular Müller glia cells later in development. Together these data provide invaluable insights into the expression dynamics of several molecules in the nonhuman primate retina and highlight the developmental advancement of the foveal region.

Growing evidence has shown that besides the protein coding genes, the non-coding elements of the genome are indispensable for maintaining the property of self-renewal in human embryonic stem cells and in cell fate determination. However, the regulatory mechanisms and the landscape of interactions between the coding and non-coding elements is poorly understood. In this work, we used weighted gene co-expression network analysis (WGCNA) on transcriptomic data retrieved from RNA-seq and small RNA-seq experiments and reconstructed the core human pluripotency network (called PluriMLMiNet) consisting of 375 mRNA, 57 lncRNA and 207 miRNAs. Furthermore, we derived networks specific to the naïve and primed states of human pluripotency (called NaiveMLMiNet and PrimedMLMiNet respectively) that revealed a set of molecular markers (RPS6KA1, ZYG11A, ZNF695, ZNF273, and NLRP2 for naive state, and RAB34, TMEM178B, PTPRZ1, USP44, KIF1A and LRRN1 for primed state) which can be used to distinguish the pluripotent state from the non-pluripotent state and also to identify the intra-pluripotency states (i.e., naïve and primed state). The lncRNA DANT1 was found to be a crucial as it formed a bridge between the naive and primed state-specific networks. Analysis of the genes neighbouring DANT1 suggested its possible role as a competing endogenous RNA (ceRNA) for the induction and maintenance of human pluripotency. This was computationally validated by predicting the missing DANT1-miRNA interactions to complete the ceRNA circuit. Here we first report that DANT1 might harbour binding sites for miRNAs hsa-miR-30c-2-3p, hsa-miR-210–3p and hsa-let-7b-5p which may influence pluripotency.