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Diatomeas , Diatomeas/metabolismo , Diatomeas/fisiología , Biofisica , Fenómenos BiofísicosRESUMEN
Introduction: Resistance against anti-Leishmania drugs (DR) has been studied for years, giving important insights into long-term adaptations of these parasites to drugs, through genetic modifications. However, microorganisms can also survive lethal drug exposure by entering into temporary quiescence, a phenomenon called drug tolerance (DT), which is rather unexplored in Leishmania. Methods: We studied a panel of nine Leishmania braziliensis strains highly susceptible to potassium antimonyl tartrate (PAT), exposed promastigotes to lethal PAT pressure, and compared several cellular and molecular parameters distinguishing DT from DR. Results and discussion: We demonstrated in vitro that a variable proportion of cells remained viable, showing all the criteria of DT and not of DR: i) signatures of quiescence, under drug pressure: reduced proliferation and significant decrease of rDNA transcription; ii) reversibility of the phenotype: return to low IC50 after removal of drug pressure; and iii) absence of significant genetic differences between exposed and unexposed lineages of each strain and absence of reported markers of DR. We found different levels of quiescence and DT among the different L. braziliensis strains. We provide here a new in-vitro model of drug-induced quiescence and DT in Leishmania. Research should be extended in vivo, but the current model could be further exploited to support R&D, for instance, to guide the screening of compounds to overcome the quiescence resilience of the parasite, thereby improving the therapy of leishmaniasis.
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Leishmania braziliensis , Leishmania , Leishmaniasis Cutánea , Humanos , Leishmania braziliensis/genética , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/parasitologíaRESUMEN
Cell context is key for cell state. Using physiologically relevant models of laminin-rich extracellular matrix (lrECM) induction of mammary epithelial cell quiescence and differentiation, we provide a landscape of the key molecules for the proliferation-quiescence decision, identifying multiple layers of regulation at the mRNA and protein levels. Quiescence occurred despite activity of Fak (also known as PTK2), Src and phosphoinositide 3-kinases (PI3Ks), suggesting the existence of a disconnecting node between upstream and downstream proliferative signalling. Pten, a lipid and protein phosphatase, fulfils this role, because its inhibition increased proliferation and restored signalling via the Akt, mTORC1, mTORC2 and mitogen-activated protein kinase (MAPK) pathways. Pten and laminin levels were positively correlated in developing murine mammary epithelia, and Pten localized apicolaterally in luminal cells in ducts and near the nascent lumen in terminal end buds. Consistently, in three-dimensional acinogenesis models, Pten was required for triggering and sustaining quiescence, polarity and architecture. The multilayered regulatory circuitry that we uncovered provides an explanation for the robustness of quiescence within a growth-suppressive microenvironment, which could nonetheless be disrupted by perturbations in master regulators such as Pten.
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(1) Background: The deployment of the bacterium Wolbachia to reduce arbovirus transmission is ongoing in several countries worldwide. When Wolbachia-carrying Aedes aegypti are released and established in the field, females may feed on dengue-infected hosts. The effects of simultaneous exposure on life-history traits of Ae. aegypti to Wolbachia wMel strain and dengue-1 virus DENV-1 remain unclear. (2) Methods: We monitored 4 groups (mosquitoes with either DENV-1 or Wolbachia, coinfected with DENV-1 and Wolbachia, as well as negative controls) to estimate Ae. aegypti survival, oviposition success, fecundity, collapsing and fertility of quiescent eggs for 12 weeks. (3) Results: Neither DENV-1 nor Wolbachia had a significant impact on mosquito survival nor on mosquito fecundity, although the last parameter showed a tendency to decrease with ageing. There was a significant decrease in oviposition success in individuals carrying Wolbachia. Wolbachia infection and storage time significantly increased egg collapse parameter on the egg viability assay, while DENV-1 had a slight protective effect on the first four weeks of storage. (4) Conclusions: Despite limitations, our results contribute to better understanding of the tripartite interaction of virus, bacteria and mosquito that may take place in field conditions and aid in guaranteeing the Wolbachia strategy success.
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Aedes , Virus del Dengue , Dengue , Wolbachia , Humanos , Animales , Femenino , FertilidadRESUMEN
The presence of cancer stem cells (CSCs) has been associated with the induction of drug resistance and disease recurrence after therapy. 5-Fluorouracil (5FU) is widely used as the first-line treatment of colorectal cancer (CRC). However, its effectiveness may be limited by the induction of drug resistance in tumor cells. The Wnt pathway plays a key role in the development and CRC progression, but it is not clearly established how it is involved in CSCs resistance to treatment. This work aimed to investigate the role played by the canonical Wnt/ß-catenin pathway in CSCs resistance to 5FU treatment. Using tumor spheroids as a model of CSCs enrichment of CRC cell lines with different Wnt/ß-catenin contexts, we found that 5FU induces in all CRC spheroids tested cell death, DNA damage, and quiescence, but in different proportions for each one: RKO spheroids were very sensitive to 5FU, while SW480 were less susceptible, and the SW620 spheroids, the metastatic derivative of SW480 cells, displayed the highest resistance to death, high clonogenic capacity, and the highest ability for regrowth after 5FU treatment. Activating the canonical Wnt pathway with Wnt3a in RKO spheroids decreased the 5FU-induced cell death. But the Wnt/ß-catenin pathway inhibition with Adavivint alone or in combination with 5FU in spheroids with aberrant activation of this pathway produced a severe cytostatic effect compromising their clonogenic capacity and diminishing the stem cell markers expression. Remarkably, this combined treatment also induced the survival of a small cell subpopulation that could exit the arrest, recover SOX2 levels, and re-grow after treatment.
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Neoplasias del Colon , Neoplasias Colorrectales , Humanos , Vía de Señalización Wnt , beta Catenina/metabolismo , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia/patología , Neoplasias del Colon/metabolismo , Línea Celular , Fluorouracilo/uso terapéutico , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Proliferación Celular , Células Madre Neoplásicas/metabolismoRESUMEN
Alternative histone acylations integrate gene expression with cellular metabolic states. Recent measurements of cellular acyl-coenzyme A (acyl-CoA) pools highlight the potential that histone post-translational modifications (PTMs) contribute directly to the regulation of metabolite pools. A metabolite-centric view throws new light onto roles and evolution of histone PTMs.
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Cromatina , Histonas , Acilcoenzima A/metabolismo , Acilación , Histonas/metabolismo , Procesamiento Proteico-PostraduccionalRESUMEN
For decades, sodium/iodide symporter NIS-mediated iodide uptake has played a crucial role in the radioactive ablation of thyroid cancer cells. NIS-based gene therapy has also become a promising tool for the treatment of tumors of extrathyroidal origin. But its applicability has been hampered by reduced expression of NIS, resulting in a moderated capacity to accumulate 131I and in inefficient ablation. Despite numerous preclinical enhancement strategies, the understanding of NIS expression within tumors remains limited. This study aims at a better understanding of the functional behavior of exogenous NIS expression in the context of malignant solid tumors that are characterized by rapid growth with an insufficient vasculature, leading to hypoxia and quiescence. Using subcutaneous HT29NIS and K7M2NIS tumors, we show that NIS-mediated uptake and NIS expression at the plasma membrane of cancer cells are impaired in the intratumoral regions. For a better understanding of the underlying molecular mechanisms induced by hypoxia and quiescence (separately and in combination), we performed experiments on HT29NIS cancer cells. Hypoxia and quiescence were both found to impair NIS-mediated uptake through mechanisms including NIS mis-localization. Modifications in the expression of proteins and metabolites involved in plasma membrane localization and in energy metabolism were found using untargeted proteomics and metabolomics approaches. In conclusion, our results provide evidence that hypoxia and quiescence impair NIS expression at the plasma membrane, and iodide uptake. Our study also shows that the tumor microenvironment is an important parameter for successful NIS-based cancer treatment.
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Peroxidases (PODs) have many biological functions during the plant life cycle. In maize kernels, endosperm PODs have been identified as biochemical contributors to resistance against Sitophilus zeamais, but their identities have not been determined. In this study, we identified these PODs and determined whether their contributions are basal or inducible. Semi-purification and LC-MS/MS analyses showed that the protein ZmPrx35 is the predominant soluble endosperm POD from kernels of Pob84-C3R. Subsequent time-course analyses after mechanical damage showed that POD activity was regulated in a fluctuating kinetics pattern and that zmprx35 mRNA expression levels reflected this pattern. After 48 h of infestation with S. zeamais or Prostephanus truncatus, soluble endosperm POD activities were 1.38- or 0.85-fold, respectively. Under the same conditions, zmprx35 expression was induced 1.61-fold (S. zeamais infestation) and 1.17-fold (P. truncatus infestation). These findings suggest that ZmPrx35 contributes to the protective responses of aleurone cells against wounding and pest attacks, which could be enhanced/repressed by insect factors. Our data also provide evidence that the mechanisms of resistance of maize Pob84-C3R kernels toward the insect pests S. zeamais and P. truncatus are independent.
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Skeletal muscle fibro-adipogenic progenitors (FAPs) are tissue-resident connective tissue cells and the main cellular source of pathological fibro-fatty scar associated with muscle disorders. Although our knowledge about skeletal muscle mesenchymal progenitor cells has exploded in the past decade, we still lack information about their origin, fate, gene regulation, function, and stemness. A recent study by Underhill and colleagues, published in Cell Stem Cell, described the last census of Hic1 mesenchymal progenitor/stem cells in skeletal muscle regeneration, providing valuable results and data to the ever-expanding community of scientists interested in tissue regeneration and fibrosis. This commentary contextualizes and summarizes these exciting new findings.
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Glioblastoma multiforme is the most aggressive primary brain tumor. Current knowledge suggests that the growth and recurrence of these tumors are due in part to the therapy-resistant glioma stem cell subpopulation, which possesses the ability for self-renewal and proliferation, driving tumor progression. In many cancers, the p16INK4a-CDK4/6-pRb pathway is disrupted in favor of cell cycle progression. In particular, the frequent deregulation of CDK4/6 in cancer positions these kinases as promising targets. Palbociclib, a potent and selective CDK4/6 inhibitor, has been approved by the FDA as a first-line treatment of advanced breast cancer and there is currently interest in evaluating its effect on other cancer types. Palbociclib has been reported to be efficient, not only at halting proliferation, but also at inducing senescence in different tumor types. In this study, we evaluated the effect of this inhibitor on four patient-derived glioma stem cell-enriched cell lines. We found that Palbociclib rapidly and effectively inhibits proliferation without affecting cell viability. We also established that in these cell lines CDK6 is the key interphase CDK for controlling cell cycle progression. Prolonged exposure to Palbociclib induced a senescent-like phenotype characterized by flattened morphology, cell cycle arrest, increased ß-galactosidase activity and induction of other senescent-associated markers. However, we found that after Palbociclib removal cell lines resumed normal proliferation, which implies they conserved their replicative potential. As a whole, our results indicate that in patient-derived glioma stem cell-enriched cell lines, Palbociclib induces a senescent-like quiescence rather than true senescence.
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Neoplasias Encefálicas/patología , Senescencia Celular/efectos de los fármacos , Glioma/patología , Células Madre Neoplásicas/patología , Piperazinas/farmacología , Piridinas/farmacología , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Glioma/metabolismo , Humanos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Fenotipo , Roscovitina/farmacologíaRESUMEN
Host plants are key factors in the survival of true bugs during unfavorable periods. The objective of this study was to evaluate the composition, diversity and abundance of pentatomid bugs in Saccharum angustifolium (Nees) Trin. (Poales: Poaceae). Plants were evaluated during the soybean and corn off--season for five years. A total of 250 plants were sampled, the true bug population was counted and used for statistical and faunistic analysis. We observed the occurrence of the species: Euschistus heros (F.), Dichelops furcatus (F.), Dichelops melacanthus (Dallas), Edessa meditabunda (F.), and Edessa ruformaginata (De Geer). Among the species, the highest population density was verified for E. meditabunda, E. heros, and D. furcatus. We also observed a direct effect of the clump diameter on the population density of E. heros, D. furcatus, and E. meditabunda. Finally, we conclude that S. angustifolium plants serve as adequate hibernacles for the survival of true bugs of economic importance during the soybean and corn off-season.(AU)
Plantas hospedeiras são fatores fundamentais na sobrevivência de percevejos durante períodos desfavoráveis. O objetivo deste trabalho foi avaliar a composição, diversidade e abundância de espécies de percevejos pentatomídeos ocorrentes em plantas de Saccharum angustifolium (Nees) Trin (Poales: Poaceae). As plantas foram avaliadas durante a entressafra de soja e milho por cinco anos. Foram amostradas 250 plantas, sendo a população de percevejos contabilizada e utilizada para a análise estatística e faunística. Observamos a ocorrência das espécies: Euschistus heros (F.), Dichelops furcatus (F.), Dichelops melacanthus (Dallas), Edessa meditabunda (F.) e Edessa ruformaginata (De Geer). Entre as espécies, foi verificada uma maior densidade populacional para E. meditabunda, E. heros e D. furcatus. Observamos, também, o efeito direto do diâmetro de touceira sobre a densidade populacional de E. heros, D. furcatus e E. meditabunda. Por fim, concluímos que plantas de S. angustifolium servem como hibernáculos adequados para a sobrevivência de percevejos de importância econômica durante a entressafra de soja e milho.(AU)
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Productos Agrícolas , Cimicidae , Saccharum , Glycine max , Brasil , Análisis de Regresión , Zea mays , Cimicidae/clasificación , Saccharum/anatomía & histologíaRESUMEN
Host plants are key factors in the survival of true bugs during unfavorable periods. The objective of this study was to evaluate the composition, diversity and abundance of pentatomid bugs in Saccharum angustifolium (Nees) Trin. (Poales: Poaceae). Plants were evaluated during the soybean and corn off--season for five years. A total of 250 plants were sampled, the true bug population was counted and used for statistical and faunistic analysis. We observed the occurrence of the species: Euschistus heros (F.), Dichelops furcatus (F.), Dichelops melacanthus (Dallas), Edessa meditabunda (F.), and Edessa ruformaginata (De Geer). Among the species, the highest population density was verified for E. meditabunda, E. heros, and D. furcatus. We also observed a direct effect of the clump diameter on the population density of E. heros, D. furcatus, and E. meditabunda. Finally, we conclude that S. angustifolium plants serve as adequate hibernacles for the survival of true bugs of economic importance during the soybean and corn off-season.(AU)
Plantas hospedeiras são fatores fundamentais na sobrevivência de percevejos durante períodos desfavoráveis. O objetivo deste trabalho foi avaliar a composição, diversidade e abundância de espécies de percevejos pentatomídeos ocorrentes em plantas de Saccharum angustifolium (Nees) Trin (Poales: Poaceae). As plantas foram avaliadas durante a entressafra de soja e milho por cinco anos. Foram amostradas 250 plantas, sendo a população de percevejos contabilizada e utilizada para a análise estatística e faunística. Observamos a ocorrência das espécies: Euschistus heros (F.), Dichelops furcatus (F.), Dichelops melacanthus (Dallas), Edessa meditabunda (F.) e Edessa ruformaginata (De Geer). Entre as espécies, foi verificada uma maior densidade populacional para E. meditabunda, E. heros e D. furcatus. Observamos, também, o efeito direto do diâmetro de touceira sobre a densidade populacional de E. heros, D. furcatus e E. meditabunda. Por fim, concluímos que plantas de S. angustifolium servem como hibernáculos adequados para a sobrevivência de percevejos de importância econômica durante a entressafra de soja e milho.(AU)
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Productos Agrícolas , Cimicidae , Saccharum , Glycine max , Brasil , Análisis de Regresión , Zea mays , Cimicidae/clasificación , Saccharum/anatomía & histologíaRESUMEN
The pathways that convert neural stem cells (NSCs) into functional neurons in the adult hippocampus are tightly regulated. In this issue of Neuron, Yeh et al. (2018) demonstrate that the activity of dentate mossy cells determines the balance between quiescence and activation of NSCs.
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Células Madre Adultas , Células-Madre Neurales , Adulto , Diferenciación Celular , Hipocampo , Humanos , Fibras Musgosas del Hipocampo , NeurogénesisRESUMEN
Cells from prokaryota to the more complex metazoans cease proliferating at some point in their lives and enter a reversible, proliferative-dormant state termed quiescence. The appearance of quiescence in the course of evolution was essential to the acquisition of multicellular specialization and compartmentalization and is also a central aspect of tissue function and homeostasis. But what makes a cell cease proliferating even in the presence of nutrients, growth factors, and mitogens? And what makes some cells "wake up" when they should not, as is the case in cancer? Here, we summarize and discuss evidence showing how microenvironmental cues such as those originating from metabolism, extracellular matrix (ECM) composition and arrangement, neighboring cells and tissue architecture control the cellular proliferation-quiescence decision, and how this complex regulation is corrupted in cancer.
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By using earthquake catalogs, previous studies have reported evidence that some changes in the spatial and temporal organization of earthquake activity are observed before and after of a main shock. These previous studies have used different approaches for detecting clustering behavior and distance-events density in order to point out the asymmetric behavior of foreshocks and aftershocks. Here, we present a statistical analysis of the seismic activity related to the M w = 8.2 earthquake that occurred on 7 September 2017 in Mexico. First, we calculated the inter-event time and distance between successive events for the period 1 January 1998 until 20 October 2017 in a circular region centered at the epicenter of the M w = 8.2 EQ. Next, we introduced the concept of pseudo-velocity as the ratio between the inter-event distance and inter-event time. A sliding window is considered to estimate some statistical features of the pseudo-velocity sequence before the main shock. Specifically, we applied the multifractal method to detect changes in the spectrum of singularities for the period before the main event on 7 September. Our results point out that the multifractality associated with the pseudo-velocities exhibits noticeable changes in the characteristics of the spectra (more narrower) for approximately three years, from 2013 until 2016, which is preceded and followed by periods with wider spectra. On the other hand, we present an analysis of patterns of seismic quiescence before the M w = 8.2 earthquake based on the Schreider algorithm over a period of 27 years. We report the existence of an important period of seismic quietude, for six to seven years, from 2008 to 2015 approximately, known as the alpha stage, and a beta stage of resumption of seismic activity, with a duration of approximately three years until the occurrence of the great earthquake of magnitude M w = 8.2 . Our results are in general concordance with previous results reported for statistics based on magnitude temporal sequences.
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Nuclear actin (N-actin) is known to participate in the regulation of gene expression. We showed previously that N-actin levels mediate the growth and quiescence of mouse epithelial cells in response to laminin-111 (LN1), a component of the mammary basement membrane (BM). We know that BM is defective in malignant cells, and we show here that it is the LN1/N-actin pathway that is aberrant in human breast cancer cells, leading to continuous growth. Photobleaching assays revealed that N-actin exit in nonmalignant cells begins as early as 30 min after LN1 treatment. LN1 attenuates the PI3K pathway leading to upregulation of exportin-6 (XPO6) activity and shuttles actin out of the nucleus. Silencing XPO6 prevents quiescence. Malignant cells are impervious to LN1 signaling. These results shed light on the crucial role of LN1 in quiescence and differentiation and how defects in the LN1/PI3K/XPO6/N-actin axis explain the loss of tissue homeostasis and growth control that contributes to malignant progression.
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Actinas/metabolismo , Neoplasias de la Mama/metabolismo , Carioferinas/metabolismo , Laminina/metabolismo , Proteínas de Neoplasias/metabolismo , Transducción de Señal , Actinas/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Humanos , Carioferinas/genética , Laminina/genética , Proteínas de Neoplasias/genética , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
Osteoblasts are one among the critical components of the endosteal bone marrow (BM) niche. In addition to hematopoietic stem cell fate, their role in leukemogenesis as well as metastasis of a variety of cancers has been demonstrated in various studies. In this regard, endosteal niche can have a dual role as an initiator and protective role against leukemia. Knowledge of growth factors, chemokines and cytokines secreted by osteoblasts as well as their interaction with signaling pathways inform our understanding of the development, prognosis, recurrence and treatment of malignant BM diseases. Clinical progress in targeting the endosteal niche is also discussed.
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Médula Ósea/patología , Transformación Celular Neoplásica/patología , Leucemia/patología , Osteoblastos/patología , Nicho de Células Madre/fisiología , Animales , HumanosRESUMEN
The eggs of pentatomid species were evaluated to parasitism by Trissolcus basalis (Wollaston) and Telenomus podisi Ashmead after storage in liquid nitrogen. Adults which emerged from stored eggs were kept at 18°C for 120 and 180 days to investigate whether adult dormancy could be associated with host egg storage in liquid nitrogen as a method of mass production of these egg parasitoids. Eggs of Nezara viridula (L.) and Acrosternum pengue (Rolston) were successfully parasitized by T. basalis, as well as Piezodorus guildinii (Westwood) and Dichelops furcatus (F.) by T. podisi. The eggs of Edessa meditabunda (F.) were not parasitized by T. basalis. The emergence of T. podisi from eggs of Euschistus heros (F.) and Podisus nigrispinus (Dallas) stored for 6 months was lower than the control. Females of T. basalis and T. podisi that emerged from stored eggs were kept in dormancy at 18°C. Longevity of T. basalis was influenced by the storage time and sex, but not by the interaction of sex and storage time. For T. podisi, longevity was influenced by the storage time, sex, and by the interaction of sex and storage time. For T. basalis, storage in liquid nitrogen did not affect the fecundity of quiescent females, while the number of parasitized eggs by T. podisi decreased after storage. By the joint use of these techniques, it is possible to optimize mass production of T. basalis so that its life cycle can be monitored and synchronized with the life cycle and availability of hosts.
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Interacciones Huésped-Parásitos , Himenópteros , Nitrógeno , Animales , Criopreservación/veterinaria , Femenino , Fertilidad , Heterópteros , Óvulo , Manejo de EspecímenesRESUMEN
El tejido sanguíneo está compuesto en un 45% aproximadamente por células y derivados de éstas, con una vida media que oscila entre 120 días para los eritrocitos y alrededor de 3 años para ciertos tipos de linfocitos. Esta pérdida es compensada gracias a la actividad del sistema hematopoyético y a la presencia de una población de células primitivas inmaduras conocidas como Células Madre Hematopoyéticas (CMHs) encargadas del proceso de hematopoyesis, activo desde el inicio de la vida fetal y que genera cerca de 2 x 1011 eritrocitos y 1010 células blancas por día (1). Las CMHs poseen la capacidad de auto-renovarse y diferenciarse a múltiples linajes, se ubican en un nicho particular y tienen marcadores de superficie que las identifican, como por ejemplo el antígeno CD34. Recientemente se ha podido avanzar en el entendimiento de la biología básica de los procesos celulares que rigen los mecanismos de auto-renovación, diferenciación y proliferación de las CMHs, y de la participación de diferentes vías de señalización (Hedgehog, Notch y Wnt) en estos procesos, los cuales controlan el comportamiento in vivo e in vitro de las CMHs. Todo esto es de vital importancia para la implementación y generación de alternativas terapéuticas con CMHs, para diversas enfermedades entre ellas las hematológicas, como por ejemplo las leucemias.
Blood tissue is composed approximately in 45% by cells and its derivatives, with a life span of around 120 days for erythrocytes and 3 years for certain type of lymphocytes. This lost is compensated with the hematopoietic system activity and the presence of an immature primitive cell population known as Hematopoietic Stem Cells (HSCs) which perform the hematopoiesis, a process that is active from the beginning of the fetal life and produces near to 2 x 1011 eritrocytes and 1010 white blood cells per day (1). Hematopoietic Stem Cells are capable of both self-renewal and differentiation into multiple lineages, are located in a particular niche and are identified by their own cell surface markers, as the CD34 antigen. Recently it has been possible to advance in the understanding of self-renewal, differentiation and proliferation processes and in the involvement of the signaling pathways Hedgehog, Notch and Wnt. Studying the influence of these mechanisms on in vivo and in vitro behavior and the basic biology of HSCs, has given valuable tools for the generation of alternative therapies for hematologic disorders as leukemias.