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MADS-domain transcription factors play pivotal roles in numerous developmental processes in Arabidopsis thaliana. While their involvement in flowering transition and floral development has been extensively examined, their functions in root development remain relatively unexplored. Here, we explored the function and genetic interaction of three MADS-box genes (XAL2, SOC1 and AGL24) in primary root development. By analyzing loss-of-function and overexpression lines, we found that SOC1 and AGL24, both critical components in flowering transition, redundantly act as repressors of primary root growth as the loss of function of either SOC1 or AGL24 partially recovers the primary root growth, meristem cell number, cell production rate, and the length of fully elongated cells of the short-root mutant xal2-2. Furthermore, we observed that the simultaneous overexpression of AGL24 and SOC1 leads to short-root phenotypes, affecting meristem cell number and fully elongated cell size, whereas SOC1 overexpression is sufficient to affect columella stem cell differentiation. Additionally, qPCR analyses revealed that these genes exhibit distinct modes of transcriptional regulation in roots compared to what has been previously reported for aerial tissues. We identified 100 differentially expressed genes in xal2-2 roots by RNA-seq. Moreover, our findings revealed that the expression of certain genes involved in cell differentiation, as well as stress responses, which are either upregulated or downregulated in the xal2-2 mutant, reverted to WT levels in the absence of SOC1 or AGL24.
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Transforming growth factor-ß (TGF-ß) and bone morphogenetic protein (BMP) signaling has fundamental roles in the regulation of the stem cell niche for both embryonic and adult stem cells. In zebrafish, male germ stem cell niche is regulated by follicle-stimulating hormone (Fsh) through different members of the TGF-ß superfamily. On the other hand, the specific roles of TGF-ß and BMP signaling pathways are unknown in the zebrafish male germ stem cell niche. Considering this lack of information, the present study aimed to investigate the pharmacological inhibition of TGF-ß (A83-01) and BMP (DMH1) signaling pathways in the presence of recombinant zebrafish Fsh using testicular explants. We also reanalyzed single cell-RNA sequencing (sc-RNA-seq) dataset from adult zebrafish testes to identify the testicular cellular sites of smad expression, and to understand the physiological significance of the changes in smad transcript levels after inhibition of TGF-ß or BMP pathways. Our results showed that A83-01 potentiated the pro-stimulatory effects of Fsh on spermatogonial differentiation leading to an increase in the proportion area occupied by differentiated spermatogonia with concomitant reduction of type A undifferentiated (Aund) spermatogonia. In agreement, expression analysis showed lower mRNA levels for the pluripotency gene pou5f3, and increased expression of dazl (marker of type B spermatogonia and spermatocyte) and igf3 (pro-stimulatory growth factor) following the co-treatment with TGF-ß inhibitor and Fsh. Contrariwise, the inhibition of BMP signaling nullified the pro-stimulatory effects of Fsh, resulting in a reduction of differentiated spermatogonia and increased proportion area occupied by type Aund spermatogonia. Supporting this evidence, BMP signaling inhibition increased the mRNA levels of pluripotency genes nanog and pou5f3, and decreased dazl levels when compared to control. The sc-RNA-seq data unveiled a distinctive pattern of smad expression among testicular cells, primarily observed in spermatogonia (smad 2, 3a, 3b, 8), spermatocytes (smad 2, 3a, 8), Sertoli cells (smad 1, 3a, 3b), and Leydig cells (smad 1, 2). This finding supports the notion that inhibition of TGF-ß and BMP signaling pathways may predominantly impact cellular components within the spermatogonial niche, namely spermatogonia, Sertoli, and Leydig cells. In conclusion, our study demonstrated that TGF-ß and BMP signaling pathways exert antagonistic roles in the zebrafish germ stem cell niche. The members of the TGF-ß subfamily are mainly involved in maintaining the undifferentiated state of spermatogonia, while the BMP subfamily promotes spermatogonial differentiation. Therefore, in the complex regulation of the germ stem cell niche by Fsh, members of the BMP subfamily (pro-differentiation) should be more predominant in the niche than those belonging to the TGF-ß (anti-differentiation). Overall, these findings are not only relevant for understanding the regulation of germ stem cell niche but may also be useful for expanding in vitro the number of undifferentiated spermatogonia more efficiently than using recombinant hormones or growth factors.
Assuntos
Pirazóis , Espermatogônias , Tiossemicarbazonas , Peixe-Zebra , Animais , Masculino , Espermatogônias/metabolismo , Peixe-Zebra/genética , Hormônio Foliculoestimulante/farmacologia , Hormônio Foliculoestimulante/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Testículo/metabolismo , Diferenciação Celular/genética , RNA Mensageiro/genética , Espermatogênese/genéticaRESUMO
In this review we discuss the concepts of the quiescent centre (QC) of the root apical meristem (RAM) and their change over time, from their formulation by F.A.L. Clowes to the present. This review is dedicated to the 100th anniversary of the birth of Clowes, and we present his short biography and a full bibliography of Clowes' work. Over time, the concept of the QC proved to be useful for the understanding of RAM organization and behaviour. We focus specifically on conceptual developments, from the organization of the QC to understanding its functions in RAM maintenance and activity, ranging from a model species, Arabidopsis thaliana, to crops. Concepts of initial cells, stem cells, and heterogeneity of the QC cells in the context of functional and structural stem cells are considered. We review the role of the QC in the context of cell flux in the RAM and the nature of quiescence of the QC cells. We discuss the origin of the QC and fluctuation of its size in ontogenesis and why the QC cells are more resistant to stress. Contemporary concepts of the organizer and stem cell niche are also considered. We also propose how the stem cell niche in the RAM can be defined in roots of a non-model species.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Proteínas de Arabidopsis/genética , Divisão Celular , Meristema , Raízes de Plantas , Nicho de Células-TroncoRESUMO
The root stem cell niche (SCN) of Arabidopsis thaliana consists of the quiescent center (QC) cells and the surrounding initial stem cells that produce progeny to replenish all the tissues of the root. The QC cells divide rather slowly relative to the initials, yet most root tissues can be formed from these cells, depending on the requirements of the plant. Hormones are fundamental cues that link such needs with the cell proliferation and differentiation dynamics at the root SCN. Nonetheless, the crosstalk between hormone signaling and the mechanisms that regulate developmental adjustments is still not fully understood. Developmental transcriptional regulatory networks modulate hormone biosynthesis, metabolism, and signaling, and conversely, hormonal responses can affect the expression of transcription factors involved in the spatiotemporal patterning at the root SCN. Hence, a complex genetic-hormonal regulatory network underlies root patterning, growth, and plasticity in response to changing environmental conditions. In this review, we summarize the scientific literature regarding the role of hormones in the regulation of QC cell proliferation and discuss how hormonal signaling pathways may be integrated with the gene regulatory network that underlies cell fate in the root SCN. The conceptual framework we present aims to contribute to the understanding of the mechanisms by which hormonal pathways act as integrators of environmental cues to impact on SCN activity.
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The ependyma of the adult spinal cord is a latent stem cell niche that is reactivated by spinal cord injury contributing new cells to the glial scar. The cellular events taking place in the early stages of the reaction of the ependyma to injury remain little understood. Ependymal cells are functionally heterogeneous with a mitotically active subpopulation lining the lateral domains of the central canal (CC) that are coupled via gap junctions. Gap junctions and connexin hemichannels are key regulators of the biology of neural progenitors during development and in adult neurogenic niches. Thus, we hypothesized that communication via connexins in the CC is developmentally regulated and may play a part in the reactivation of this latent stem cell niche after injury. To test these possibilities, we combined patch-clamp recordings of ependymal cells with immunohistochemistry for various connexins in the neonatal and the adult (P > 90) normal and injured spinal cord of male and female mice. We find that coupling among ependymal cells is downregulated as postnatal development proceeds but increases after injury, resembling the immature CC. The increase in gap junction coupling in the adult CC was paralleled by upregulation of connexin 26, which correlated with the resumption of proliferation and a reduction of connexin hemichannel activity. Connexin blockade reduced the injury-induced proliferation of ependymal cells. Our findings suggest that connexins are involved in the early reaction of ependymal cells to injury, representing a potential target to improve the contribution of the CC stem cell niche to repair.SIGNIFICANCE STATEMENT Ependymal cells in the adult spinal cord are latent progenitors that react to injury to support some degree of endogenous repair. Understanding the mechanisms by which these progenitor-like cells are regulated in the aftermath of spinal cord injury is critical to design future manipulations aimed at improving healing and functional recovery. Gap junctions and connexin hemichannels are key regulators of the biology of neural progenitors during development and in adult neurogenic niches. We find here that connexin signaling in the ependyma changes after injury of the adult spinal cord, functionally resembling the immature active-stem cell niche of neonatal animals. Our findings suggest that connexins in ependymal cells are potential targets to improve self-repair of the spinal cord.
Assuntos
Conexinas/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Nicho de Células-Tronco/fisiologia , Fatores Etários , Sequência de Aminoácidos , Animais , Animais Recém-Nascidos , Membrana Celular/fisiologia , Permeabilidade da Membrana Celular , Conexinas/antagonistas & inibidores , Epêndima/citologia , Epêndima/crescimento & desenvolvimento , Feminino , Corantes Fluorescentes/farmacocinética , Junções Comunicantes/fisiologia , Hidrogéis , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/antagonistas & inibidores , Técnicas de Patch-Clamp , Peptídeos/química , Peptídeos/farmacologia , Poloxâmero/farmacologia , Distribuição AleatóriaRESUMO
During plant development, morphogenetic processes rely on the activity of meristems. Meristem homeostasis depends on a complex regulatory network constituted by different factors and hormone signaling that regulate gene expression to coordinate the correct balance between cell proliferation and differentiation. ULTRAPETALA1, a transcriptional regulatory protein described as an Arabidopsis Trithorax group factor, has been characterized as a regulator of the shoot and floral meristems activity. Here, we highlight the role of ULTRAPETALA1 in root stem cell niche maintenance. We found that ULTRAPETALA1 is required to regulate both the quiescent center cell division rate and auxin signaling at the root tip. Furthermore, ULTRAPETALA1 regulates columella stem cell differentiation. These roles are independent of the ARABIDOPSIS TRITHORAX1, suggesting a different mechanism by which ULTRAPETALA1 can act in the root apical meristem of Arabidopsis. This work introduces a new component of the regulatory network needed for the root stem cell niche maintenance.
Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/citologia , Arabidopsis/metabolismo , Raízes de Plantas/citologia , Nicho de Células-Tronco , Células-Tronco/citologia , Fatores de Transcrição/metabolismo , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Ciclo Celular , Divisão Celular , Regulação da Expressão Gênica de Plantas , Histona-Lisina N-Metiltransferase , Ácidos Indolacéticos/metabolismo , Meristema/citologia , Meristema/genética , Raízes de Plantas/genética , Transdução de Sinais , Nicho de Células-Tronco/genética , Células-Tronco/metabolismo , Fatores de Transcrição/genéticaRESUMO
In contrast to the bulk of the tumor, a subset of cancer cells called cancer stem cells (CSC; or tumor-initiating cells) is characterized by self-renewal, unlimited proliferative potential, expression of multidrug resistance proteins, active DNA repair capacity, apoptosis resistance, and a considerable developmental plasticity. Due to these properties, CSCs display increased resistance to chemo- and radiotherapy. Recent findings indicate that aberrant functions of proteoglycans (PGs) and glycosaminoglycans (GAGs) contribute substantially to the CSC phenotype and therapeutic resistance. In this review, we summarize how the diverse functions of the glycoproteins and carbohydrates facilitate acquisition and maintenance of the CSC phenotype, and how this knowledge can be exploited to develop novel anticancer therapies. For example, the large transmembrane chondroitin sulfate PG NG2/CSPG4 marks stem cell (SC) populations in brain tumors. Cell surface heparan sulfate PGs of the syndecan and glypican families modulate the stemness-associated Wnt, hedgehog, and notch signaling pathways, whereas the interplay of hyaluronan in the SC niche with CSC CD44 determines the maintenance of stemness and promotes therapeutic resistance. A better understanding of the molecular mechanisms by which PGs and GAGs regulate CSC function will aid the development of targeted therapeutic approaches which could avoid relapse after an otherwise successful conventional therapy. Chimeric antigen receptor T cells, PG-primed dendritic cells, PG-targeted antibody-drug conjugates, and inhibitory peptides and glycans have already shown highly promising results in preclinical models.
Assuntos
Glipicanas/metabolismo , Receptores de Hialuronatos/metabolismo , Células-Tronco Neoplásicas/metabolismo , Sindecanas/metabolismo , Animais , Resistencia a Medicamentos Antineoplásicos , Glipicanas/genética , Humanos , Receptores de Hialuronatos/genética , Ácido Hialurônico/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos da radiação , Tolerância a Radiação , Transdução de Sinais , Sindecanas/genéticaRESUMO
The plant hormone ethylene induces auxin biosynthesis and transport and modulates root growth and branching. However, its function on root stem cells and the identity of interacting factors for the control of meristem activity remains unclear. Genetic analysis for primary root growth in wild-type (WT) Arabidopsis thaliana seedlings and ethylene-related mutants showed that the loss-of-function of CONSTITUTIVE TRIPLE RESPONSE1 (CTR1) inhibits cell division and elongation. This phenotype is associated with an increase in the expression of the auxin transporter PIN2 and a drastic decrease in the expression of key factors for stem cell niche maintenance such as PLETHORA1, SHORT ROOT and SCARECROW. While the root stem cell niche is affected in ctr1 mutants, its maintenance is severely compromised in the ctr1-1eir1-1(pin2) double mutant, in which an evident loss of proliferative capacity of the meristematic cells leads to a fully differentiated root meristem shortly after germination. Root traits affected in ctr1-1 mutants could be restored in ctr1-1ein2-1 double mutants. These results reveal that ethylene perception via CTR1 and EIN2 in the root modulates the proliferative capacity of root stem cells via affecting the expression of genes involved in the two major pathways, AUX-PIN-PLT and SCR-SHR, which are key factors for proper root stem cell niche maintenance.
Assuntos
Proteínas de Arabidopsis/metabolismo , Plântula/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Etilenos/metabolismo , Meristema/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Raízes de Plantas/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Collared peccaries (Tayassu tajacu) present a unique testis cytoarchitecture, where Leydig cells (LC) are mainly located in cords around the seminiferous tubules (ST) lobes. This peculiar arrangement is very useful to better investigate and understand the role of LC in spermatogonial stem cells (SSCs) biology and niche. Recent studies from our laboratory using adult peccaries have shown that the undifferentiated type A spermatogonia (Aund or SSCs) are preferentially located in ST regions adjacent to the intertubular compartment without LC. Following these studies, our aims were to investigate the collared peccary postnatal testis development, from birth to adulthood, with emphasis on the establishment of LC cytoarchitecture and the SSCs niche. Our findings demonstrated that the unique LC cytoarchitecture is already present in the neonate peccary's testis, indicating that this arrangement is established during fetal development. Based on the most advanced germ cell type present at each time period evaluated, puberty (the first sperm release in the ST lumen) in this species was reached at around one year of age, being preceded by high levels of estradiol and testosterone and the end of Sertoli cell proliferation. Almost all gonocytes and SSCs expressed Nanos1, Nanos2 and GFRA1. The analysis of SSCs preferential location indicated that the establishment of SSCs niche is coincident with the occurrence of puberty. Taken together, our findings reinforced and extended the importance of the collared peccary as an animal model to investigate testis function in mammals, particularly the aspects related to testis organogenesis and the SSCs biology and niche.
Assuntos
Artiodáctilos/crescimento & desenvolvimento , Biomarcadores/metabolismo , Espermatogônias/citologia , Nicho de Células-Tronco , Células-Tronco/metabolismo , Testículo/crescimento & desenvolvimento , Animais , Peso Corporal , Hormônios/metabolismo , Masculino , Tamanho do Órgão , Fenótipo , Túbulos Seminíferos/metabolismo , Células de Sertoli/metabolismo , Espermatogênese , Espermatogônias/metabolismo , Testículo/anatomia & histologia , Testículo/metabolismoRESUMO
ABSTRACT Various approaches have been taken to improve our knowledge of the microenvironmental regulation of limbal epithelial stem cells. Researchers have extensively investigated the roles of growth factors, survival factors, cytokines, enzymes, and permeable molecules secreted by the limbal cells. However, recent evidence suggests that stem cell fate (i.e., self-renewal or differentiation) can also be influenced by biophysical and mechanical cues related to the supramolecular organization and the liquid crystalline (mesophase) nature of the stromal extracellular matrix. These cues can be sensed by stem cells and transduced into intracellular biochemical and functional responses, a process known as mechanotransduction. The objective of this review is to offer perspectives on the supramolecular microenvironmental regulation of limbal epithelial stem cells and the differentiation of their progeny.
RESUMO Muitas abordagens têm sido utilizadas para ampliar entendimentos sobre a regulação microambiental das células tronco epiteliais limbais. Neste contexto, pesquisadores têm exaustivamente investigado a participação de fatores de crescimento, fatores de sobrevida, citocinas, enzimas e moléculas permeáveis secretadas pelas células limbais. Entretanto, evidências recentes sugerem que o destino (ie. autorrenovação ou recrutamento para a via de diferenciação) das células tronco também sofre influência de estímulos biofísicos ou mecânicos relacionados à organização supramolecular e à natureza liquido-cristalina (mesofases) da matriz extracelular estromal. Esses estímulos podem ser percebidos e traduzidos pelas células tronco em sinais bioquímicos que geram respostas funcionais, através de um processo designado de mecanotransdução. Objetiva-se, com a presente revisão, oferecer ao leitor perspectivas supramoleculares sobre a regulação microambiental das células tronco epiteliais limbais e a diferenciação de sua progênie.
Assuntos
Humanos , Células-Tronco/fisiologia , Diferenciação Celular/fisiologia , Limbo da Córnea/citologia , Epitélio Corneano/citologia , Mecanotransdução Celular/fisiologia , Matriz Extracelular/fisiologia , Epitélio Corneano/fisiologia , Nicho de Células-Tronco/fisiologiaRESUMO
Evidence presented over the last few years indicates that the hematopoietic stem cell (HSC) compartment comprises not just one but a number of different cell populations. Based on HSCs' proliferation and engraftment potential, it has been suggested that there are two classes of HSC, with long- and short-term engraftment potential. HSC heterogeneity seems to involve differentiation capacities as well, since it has been shown that some HSC clones are able to give rise to both myeloid and lymphoid progeny, whereas others are lymphoid deficient. It has been recognized that HSC function depends on intrinsic cell regulators, which are modulated by external signals. Among the former, we can include transcription factors and non-coding RNAs as well as epigenetic modifiers. Among the latter, cytokines and extracellular matrix molecules have been implicated. Understanding the elements and mechanisms that regulate HSC populations is of significant relevance both in biological and in clinical terms, and research in this area still has to face several complex and exciting challenges.
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It has been one and a half centuries since Enrico Sertoli published the seminal discovery of the testicular 'nurse cell', not only a key cell in the testis, but indeed one of the most amazing cells in the vertebrate body. In this review, we begin by examining the three phases of morphological research that have occurred in the study of Sertoli cells, because microscopic anatomy was essentially the only scientific discipline available for about the first 75 years after the discovery. Biochemistry and molecular biology then changed all of biological sciences, including our understanding of the functions of Sertoli cells. Immunology and stem cell biology were not even topics of science in 1865, but they have now become major issues in our appreciation of Sertoli cell's role in spermatogenesis. We end with the universal importance and plasticity of function by comparing Sertoli cells in fish, amphibians, and mammals. In these various classes of vertebrates, Sertoli cells have quite different modes of proliferation and epithelial maintenance, cystic vs. tubular formation, yet accomplish essentially the same function but in strikingly different ways.
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Andrologia/história , Células de Sertoli , Animais , História do Século XIX , Humanos , MasculinoRESUMO
Central nervous system (CNS) impairment is commonly involved in leukemia, as it can be observed upon onset or relapse of the disease. It is associated with poor prognosis and is a challenging clinical problem. The objective of this paper was to provide a characterization of the CNS niche in leukemia, to elucidate the culprits of CNS involvement, including diagnostic micro RNAs (miRs) and early leukemia prognosis. CNS niche is a proper location for homing of leukemic stem cells, thus representing a candidate target in the treatment of leukemia. Recent advances in the study of leukemia hallmarks have enlightened miRs as novel biomarkers for diagnosis and detection of CNS involvement in leukemia, thus providing the opportunity to develop novel therapeutic approaches. Given the importance of prognosis and early diagnosis of CNS involvement in leukemias as well as the severe side effects of current treatments, diagnostic and therapeutic approaches should focus on identification and inhibition of the factors contributing to CNS involvement, including CXCR3, P-selectin glycoprotein ligand-1 and MCP1. MiRs such as miR-221 and miR-222 are emerging as potential tools for an innovative non-invasive therapy of CNS in leukemia affected patients.
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Neoplasias do Sistema Nervoso Central/patologia , Leucemia/patologia , Células-Tronco Neoplásicas/patologia , Nicho de Células-Tronco , Movimento Celular , HumanosRESUMO
AIM: To detect cells expressing the stem cell marker ALDH1 (aldehyde dehydrogenase1) in the pulp of human permanent teeth and to investigate the expression of ALDH1 in isolated dental pulp cells. METHODOLOGY: Pulp tissue was collected and processed for immunohistochemistry to detect ALDH1-, STRO-1- and CD90-positive cells. In addition, cells were isolated and analysed by flow cytometry for ALDH1 activity and for the cell surface markers CD44, CD73, CD90, STRO-1 and CD45. Cells were also examined for multidifferentiation capacity. Within these cells, an ALDH1(+) cell subpopulation was selected and evaluated for multidifferentiation capacity. RESULTS: The immunohistochemistry analyses showed that ALDH1-, CD90- and STRO-1-positive cells were located mainly in the perivascular areas and nerve fibres of dental pulps. Cells on the fifth passage had high expression for CD44, CD73 and CD90, whereas moderate labelling was observed for STRO-1 and ALDH1 in flow cytometry analysis. On the same passages, cells were able to differentiate into osteogenic, adipogenic and chondrogenic lineages. The ALDH1(+) cell subpopulation also demonstrated multilineage differentiation ability. CONCLUSIONS: Dental pulp stem cells reside in the vicinity of blood vessels and nerve fibres, indicating the possible existence of more than one stem cell niche in dental pulps. Furthermore, ALDH1 was expressed by isolated dental pulp cells, which had mesenchymal stem cell characteristics. Thus, it can be suggested that ALDH1 may be used as a DPSC marker.
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Polpa Dentária/citologia , Isoenzimas/metabolismo , Retinal Desidrogenase/metabolismo , Células-Tronco , Adolescente , Adulto , Família Aldeído Desidrogenase 1 , Antígenos de Superfície/metabolismo , Biomarcadores/metabolismo , Vasos Sanguíneos/metabolismo , Polpa Dentária/irrigação sanguínea , Polpa Dentária/metabolismo , Humanos , Dente Serotino , Antígenos Thy-1/metabolismo , Adulto JovemRESUMO
Mammalian spermatogenesis is a complex process in which spermatogonial stem cells of the testis (SSCs) develop to ultimately form spermatozoa. In the seminiferous epithelium, SSCs self-renew to maintain the pool of stem cells throughout life, or they differentiate to generate a large number of germ cells. A balance between SSC self-renewal and differentiation is therefore essential to maintain normal spermatogenesis and fertility. Stem cell homeostasis is tightly regulated by signals from the surrounding microenvironment, or SSC niche. By physically supporting the SSCs and providing them with these extrinsic molecules, the Sertoli cell is the main component of the niche. Earlier studies have demonstrated that GDNF and CYP26B1, produced by Sertoli cells, are crucial for self-renewal of the SSC pool and maintenance of the undifferentiated state. Down-regulating the production of these molecules is therefore equally important to allow germ cell differentiation. We propose that NOTCH signaling in Sertoli cells is a crucial regulator of germ cell fate by counteracting these stimulatory factors to maintain stem cell homeostasis. Dysregulation of this essential niche component can lead by itself to sterility or facilitate testicular cancer development.
Assuntos
Masculino , Animais , Células Germinativas/enzimologia , Células-Tronco/química , HomeostaseRESUMO
Mammalian spermatogenesis is a complex process in which spermatogonial stem cells of the testis (SSCs) develop to ultimately form spermatozoa. In the seminiferous epithelium, SSCs self-renew to maintain the pool of stem cells throughout life, or they differentiate to generate a large number of germ cells. A balance between SSC self-renewal and differentiation is therefore essential to maintain normal spermatogenesis and fertility. Stem cell homeostasis is tightly regulated by signals from the surrounding microenvironment, or SSC niche. By physically supporting the SSCs and providing them with these extrinsic molecules, the Sertoli cell is the main component of the niche. Earlier studies have demonstrated that GDNF and CYP26B1, produced by Sertoli cells, are crucial for self-renewal of the SSC pool and maintenance of the undifferentiated state. Down-regulating the production of these molecules is therefore equally important to allow germ cell differentiation. We propose that NOTCH signaling in Sertoli cells is a crucial regulator of germ cell fate by counteracting these stimulatory factors to maintain stem cell homeostasis. Dysregulation of this essential niche component can lead by itself to sterility or facilitate testicular cancer development.(AU)
Assuntos
Animais , Masculino , Células-Tronco/química , Células Germinativas/enzimologia , HomeostaseRESUMO
Mammalian spermatogenesis is a complex process in which spermatogonial stem cells of the testis (SSCs) develop to ultimately form spermatozoa. In the seminiferous epithelium, SSCs self-renew to maintain the pool of stem cells throughout life, or they differentiate to generate a large number of germ cells. A balance between SSC self-renewal and differentiation is therefore essential to maintain normal spermatogenesis and fertility. Stem cell homeostasis is tightly regulated by signals from the surrounding microenvironment, or SSC niche. By physically supporting the SSCs and providing them with these extrinsic molecules, the Sertoli cell is the main component of the niche. Earlier studies have demonstrated that GDNF and CYP26B1, produced by Sertoli cells, are crucial for self-renewal of the SSC pool and maintenance of the undifferentiated state. Down-regulating the production of these molecules is therefore equally important to allow germ cell differentiation. We propose that NOTCH signaling in Sertoli cells is a crucial regulator of germ cell fate by counteracting these stimulatory factors to maintain stem cell homeostasis. Dysregulation of this essential niche component can lead by itself to sterility or facilitate testicular cancer development.
RESUMO
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm related to the presence of the BCR-ABL1 fusion gene, linked to t (9;22) (q34;q11). It is originated from an abnormal hematopoietic stem cell, which is characterized as its normal counterparts by long-term self-renewal and multi-lineage differentiation. Both leukemic and quiescent normal hematopoietic stem cells preferentially reside in the osteoblastic niche. Mesenchymal stromal cells (MSC) are located near them, playing a critical role in their regulation. Currently, with tyrosine kinase inhibitor (TKI) therapy, long term clinical responses are achieved in most CML cases. However, late treatment failures may be observed related to the persistence of leukemic stem cells. The interactions between the leukemic stem cell and the microenvironment may be responsible in part for these events. We review the interactions between the leukemic stem cell and BM stroma and its potential clinical and therapeutic implications.
Assuntos
Humanos , Medula Óssea/fisiopatologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/fisiopatologia , Células-Tronco Mesenquimais/fisiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológicoRESUMO
Roots have both indeterminate and determinate developmental programs. The latter is preceded by the former. It is not well understood how the indeterminacy-to-determinacy switch (IDS) is regulated. We isolated a moots koom2 (mko2; 'short root' in Mayan) Arabidopsis thaliana mutant with determinate primary root growth and analyzed the root apical meristem (RAM) behavior using various marker lines. Deep sequencing and genetic and pharmacological complementation permitted the identification of a point mutation in the FOLYLPOLYGLUTAMATE SYNTHETASE1 (FPGS1) gene responsible for the mko2 phenotype. Wild-type FPGS1 is required to maintain the IDS in the 'off' state. When FPGS1 function is compromised, the IDS is turned on and the RAM becomes completely consumed. The polyglutamate-dependent pathway of the IDS involves activation of the quiescent center independently of auxin gradients and regulatory modules participating in RAM maintenance (WUSCHEL-RELATED HOMEOBOX5 (WOX5), PLETHORA, and SCARECROW (SCR)). The mko2 mutation causes drastic changes in folate metabolism and also affects lateral root primordium morphogenesis but not initiation. We identified a metabolism-dependent pathway involved in the IDS in roots. We suggest that the root IDS represents a specific developmental pathway that regulates RAM behaviour and is a different level of regulation in addition to RAM maintenance.
Assuntos
Arabidopsis/genética , Ácido Fólico/metabolismo , Peptídeo Sintases/genética , Arabidopsis/citologia , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Meristema/citologia , Meristema/genética , Meristema/crescimento & desenvolvimento , Meristema/metabolismo , Peptídeo Sintases/metabolismo , Raízes de Plantas/citologia , Raízes de Plantas/genética , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Plantas Geneticamente Modificadas , Mutação Puntual , Transdução de Sinais , Nicho de Células-TroncoRESUMO
No final do século 19, o neurônio foi descrito como a unidade funcional básica do sistema nervoso e sua formação era considerada inexistente na fase adulta, explicando a ausência de recuperação significativa em doenças neurológicas. Evidências de geração de neurônios em mamíferos adultos surgiram na década de 1960 e foram confirmadas três décadas depois. Atualmente, predomina a visão de que mamíferos adultos possuem dois nichos neurogênicos independentes: a zona subventricular (ZSV) e a zona subgranular (ZSG) do giro denteado. No entanto, a existência de nichos neurogênicos em humanos adultos é controversa. Nossa hipótese foi de que o mapeamento de nichos neurogênicos no lobo temporal humano poderia esclarecer aspectos sobre a neurogênese adulta. A detecção destes nichos foi buscada em 28 lobos temporais através de imuno-histoquímica para nestina, o marcador mais comum de células-tronco neurais, que são aquelas capazes de se autorrenovar e de gerar novas células neurais. A neurogênese foi pesquisada no hipocampo pelo uso de DCX (do inglês "doublecortin"), o principal marcador de neuroblastos e neurônios imaturos. Nestina foi observada em uma camada contínua formada pela ZSV, zona subpial do lobo temporal medial e ZSG, terminando no subículo. A partir do subículo, uma intensa expressão de DCX ocorreu através da principal via eferente do hipocampo até a fímbria. A visão panorâmica das marcações por nestina e DCX mostrava em conjunto uma linha que circundava as estruturas límbicas do lobo temporal. Por isto, foi denominada linha externa de células do sistema límbico (LECEL). Uma possível explicação para os resultados é que a LECEL seja um nicho neurogênico no qual a ZSV, a zona subpial do lobo temporal medial e a ZSG formam uma unidade contendo células-tronco neurais que se diferenciam em neurônios no subículo. Curiosamente, a área identificada previamente como sendo a corrente migratória rostral humana (formada por células neurais imaturas migrando a partir da...
At the end of the 19th century, the neuron was described as the basic functional unit of the nervous system. The formation of neurons was thought to be absent in adulthood, thus explaining the lack of significant recovery from neurological diseases. Evidence for the generation of neurons in adult mammals was reported in the 1960s and confirmed three decades later. Currently, the prevailing view is that adult mammals harbour two neurogenic niches: the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ). Nonetheless, the existence of these niches in adult humans is controversial. We hypothesised that mapping neurogenic niches in the human temporal lobe could clarify this issue. The presence of neurogenic niches was examined in 28 temporal lobes via immunostaining for nestin, the most common marker for neural stem cells, which are cells with the capacities of self-renewal and the generation of neural cells. The presence of neurogenesis was examined in the hippocampus with doublecortin (DCX), a prominent marker for neuroblasts and immature neurons. Nestin was observed in a continuous layer that was formed by the SVZ, the subpial zone of the medial temporal lobe and the SGZ, terminating in the subiculum. In the subiculum, remarkable DCX expression was observed through the principal efferent pathway of the hippocampus to the fimbria. A panoramic view of nestin and DCX staining collectively displayed a line that surrounded the limbic structures of the temporal lobe. Hence, we termed it the external line of cells of the limbic system (EXCEL). A possible explanation for the results is that the EXCEL is a neurogenic niche, in which the SVZ, the subpial zone of the medial temporal lobe and the SGZ form a unit containing neural stem cells that differentiate into neurons in the subiculum. Curiously, the area previously identified as the human rostral migratory stream (formed by immature neural cells that migrate from the SVZ of the frontal horn)...