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Unilateral rnurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neuropathology and behavioral deficits in parkinsonian rats withα-synucleinopathy

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neural Regeneration Research 2024年第9期19卷 2057-2067页

作者： Bismark Gatica-Garcia Michael J.Bannon Irma Alicia Martínez-Dávila Luis O.Soto-Rojas David Reyes-Corona Lourdes Escobedo Minerva Maldonado-Berny ME Gutierrez-Castillo Armando J.Espadas-Alvarez Manuel A.Fernandez-Parrilla Juan U.Mascotte-Cruz CP Rodríguez-Oviedo Irais E.Valenzuela-Arzeta Claudia Luna-Herrera Francisco E.Lopez-Salas Jaime Santoyo-Salazar Daniel Martinez-Fong departamento de Fisiología Biofísica y NeurocienciasCentro de Investigación y de Estudios AvanzadosCiudad de MéxicoMéxico department of Pharmacology Wayne State University School of MedicineDetroitMIUSA Laboratorio de Patogénesis Molecular Carrera Médico CirujanoFacultad de Estudios Superiores IztacalaUniversidad Nacional Autónoma de MéxicoTlalnepantla de BazMéxico Red de Medicina para la Educación y desarrollo y la investigación Científica de Iztacala(Red MEDICI) Carrera Médico CirujanoFacultad de Estudios Superiores IztacalaUniversidad Nacional Autónoma de MéxicoTlalnepantla de BazMéxico nanoparticle Therapy Institute AguascalientesMéxico departamento de Biociencias e Ingeniería Centro Interdisciplinario de Investigaciones y Estudios sobre Medio Ambiente y DesarrolloInstituto Politécnico NacionalCiudad de MéxicoMéxico Escuela nacional de Medicina y Homeopatía Instituto Politécnico NacionalCiudad de MéxicoMéxico departamento de Fisiología Escuela Nacional de Ciencias BiológicasInstituto Politécnico NacionalCiudad de MéxicoMéxico departamento de Biología Molecular y Biotecnología Instituto de Investigaciones BiomédicasUniversidad Nacional Autónoma de MéxicoCiudad de MéxicoMéxico departamento de Física Centro de Investigación y de Estudios AvanzadosCiudad de MéxicoMéxico Programa de nanociencias y nanotecnología Centro de Investigación y de Estudios AvanzadosCiudad de MéxicoMéxico

Parkinsonism by unilateral,intranigralβ-sitosterolβ-D-glucoside administration in rats is distinguished in that theα-synuclein insult begins unilaterally but spreads bilaterally and increases in severity over time,thus replicating several clinical features of Parkinson’s disease,a typicalα-synucleinopathy.As nurr1 repressesα-synuclein,we evaluated whether unilateral transfected of rnurr1-V5 transgene via neurotensin-polyplex to the substantia nigra on day 30 after unilateralβ-sitosterolβ-D-glucoside lesion could affect bilateral neuropathology and sensorimotor deficits on day 30 post-transfection.This study found that rnurr1-V5 expression but not that of the green fluorescent protein(the negative control)reducedβ-sitosterolβ-D-glucoside-induced neuropathology.Accordingly,a bilateral increase in tyrosine hydroxylase-positive cells and arborization occurred in the substantia nigra and increased tyrosine hydroxylase-positive ramifications in the striatum.In addition,tyrosine hydroxylase-positive cells displayed less senescence markerβ-galactosidase and more neuron-cytoskeleton markerβIII-tubulin and brain-derived neurotrophic factor.A significant decrease in activated microglia(positive to ionized calcium-binding adaptor molecule 1)and neurotoxic astrocytes(positive to glial fibrillary acidic protein and complement component 3)and increased neurotrophic astrocytes(positive to glial fibrillary acidic protein and S100 calcium-binding protein A10)also occurred in the substantia nigra.These effects followed the bilateral reduction inα-synuclein aggregates in the nigrostriatal system,improving sensorimotor behavior.Our results show that unilateral rnurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neurodegeneration(senescence and loss of neuron-cytoskeleton and tyrosine hydroxylase-positive cells),neuroinflammation(activated microglia,neurotoxic astrocytes),α-synuclein aggregation,and sensorimotor deficits.Increased neurotrophic astrocytes and brain-derived neurotrophic factor can mediate t

关键词： A1 astrocytes A2 astrocytes gene therapy microglia motor deficits nanoparticles neurodegeneration neuroinflammation senescence α-synuclein aggregates

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Geochemical elements in suspended particulate matter of Ensenada de La Paz Lagoon,Baja California Peninsula,Mexico:Sources,distribution,mass balance and ecotoxicological risks

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Journal of Environmental Sciences 2024年第2期136卷 422-436页

作者： Sandra Soledad Morales-García Pilar de Acacia Pérez-Escamilla Suresh Babu Sujitha Pichaimani Godwyn-Paulson Andrés Felipe Zuniga-Cabezas Muthuswamy Ponniah Jonathan instituto politécnico nacional(IPn) Centro Mexicano para la Producción más Limpia(CMPL)Av.Acueducto s/nCol.Barrio la Laguna TicománDel Gustavo A.MaderoC.P.07340Ciudad de MéxicoMexico instituto politécnico nacional(IPn) Escuela Superior de Ingeniería y Arquitectura(ESIA)Unidad Ticomán***án 600Delg.Gustavo A.MaderoC.P.07340Ciudad de México(CDMX)Mexico instituto politécnico nacional(IPn) Centro Interdisciplinario de Investigaciones y Estudios sobre Medio Ambiente y Desarrollo(CIIEMAD)Calle 30 de Junio de 1520Barrio la Laguna TicománDel.Gustavo A.MaderoC.P.07340Ciudad de MéxicoMéxico

The present study aimed to evaluate multi-element concentrations(Al,As,Ca,Cd,Co,Cr,Cu,Fe,Mg,Mn,Mo,ni,Pb,Sr)in suspended particulate material(SPM)collected from Ensenada de La Paz(ELP)lagoon,Baja California Sur,Mexico in two different periods(September and May)to comprehend their origin,geochemical behavior,mass transfer and associated ecotoxicological risks.The 24 hr variation coefficient of volumetric SPM levels were found to be 51.7%in September and 40.5%in May,signifying the effects of oceanic waters.The calculated enrichment factor(EF)values for all the studied elements were of higher magnitude because of the high surface area and oxide nature of SPM,and in this study,Mo had the highest EF of 46.77 probably due to its origin from continental weathering.From the ecotoxicological perspective,the integrated toxic risk index revealed low toxic risk to the benthic community.However,the mean-ERM-Quotient calculated using the particulate concentrations of As,Cd,Cr,Cu,ni,Pb indicated 9%probability of toxicity to biota.The comprehensive geochemical and ecotoxicological assessment of particulate metal concentrations in the ELP lagoon signify low to moderate contamination.

关键词： Suspended particulate material Heavy metals Risk assessment Mass transfer Ensenada de La Paz

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Metal-modulated epitaxy of Mg-doped Al_(0.80)In_(0.20)n-based layer for application as the electron blocking layer in deep ultraviolet light-emitting diodes

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Journal of Semiconductors 2024年第5期45卷 80-89页

作者： Horacio Irán Solís-Cisneros Carlos Alberto Hernández-Gutiérrez Enrique Campos-González Máximo López-López Optomechatronics Group Tecnológico Nacional de México Campus Tuxtla Gutiérrezcarretera Panamericana 1080C.P.29050Tuxtla GutiérrezChiapasMéxico departamento de Física Instituto Nacional de Investigaciones NuclearesCarretera México-Toluca s/nC.P.52750La Marquesa OcoyoacacMéxico departamento de Física Centro de Investigación y estudios Avanzados del Instituto Politécnico NacionalAv.Instituto Politécnico Nacional 2508San Pedro ZacatencoGustavo A.Madero07360 Ciudad de MéxicoCDMXMéxico

This work reports the growth and characterization of p-AlInn layers doped with Mg by plasma-assisted molecular beam epitaxy(PAMBE).AlInn was grown with an Al molar fraction of 0.80 by metal-modulated epitaxy(MME)with a thickness of 180 nm on Si(111)substrates using Aln as buffer layers.Low substrate temperatures were used to enhance the incorporation of indium atoms into the alloy without clustering,as confirmed by X-ray diffraction(XRD).Cathodoluminescence measurements revealed ultraviolet(UV)range emissions.Meanwhile,Hall effect measurements indicated a maximum hole mobility of 146 cm^(2)/(V∙s),corresponding to a free hole concentration of 1.23×10^(19)cm^(−3).The samples were analyzed by X-ray photoelectron spectroscopy(XPS)estimating the alloy composition and extracting the Fermi level by valence band analysis.Mg-doped AlInn layers were studied for use as the electron-blocking layer(EBL)in LED structures.We varied the Al composition in the EBL from 0.84 to 0.96 molar fraction to assess its theoretical effects on electroluminescence,carrier concentration,and electric field,using SILVACO Atlas.The results from this study highlight the importance and capability of producing high-quality Mg-doped p-AlInn layers through PAMBE.Our simulations suggest that an Al content of 0.86 is optimal for achieving desired outcomes in electroluminescence,carrier concentration,and electric field.

关键词： metal-modulated epitaxy AlInn DUV-LED EBL simulation

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Hypothalamic circuits and aging:keeping the circadian clock updated

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neural Regeneration Research 2024年第9期19卷 1919-1928页

作者： Rosa Vázquez-Lizarraga Lucia Mendoza-Viveros Carolina Cid-Castro Sareni Ruiz-Montoya Erick Carreño-Vázquez Ricardo Orozco-Solis instituto nacional de Medicina Genómica(InMEGEn) México CityMéxico centro de Investigacíon sobre el Envejecimiento Centro de Investigacíon y de Estudios Avanzados(CIE-CINVESTAV)México CityMéxico instituto de investigaciones Biomédicas Universidad Nacional Autónoma de México UNAMMéxico CityMéxico

Over the past century,age-related diseases,such as cancer,type-2 diabetes,obesity,and mental illness,have shown a significant increase,negatively impacting overall quality of life.Studies on aged animal models have unveiled a progressive discoordination at multiple regulatory levels,including transcriptional,translational,and post-translational processes,resulting from cellular stress and circadian derangements.The circadian clock emerges as a key regulator,sustaining physiological homeostasis and promoting healthy aging through timely molecular coordination of pivotal cellular processes,such as stem-cell function,cellular stress responses,and inter-tissue communication,which become disrupted during aging.Given the crucial role of hypothalamic circuits in regulating organismal physiology,metabolic control,sleep homeostasis,and circadian rhythms,and their dependence on these processes,strategies aimed at enhancing hypothalamic and circadian function,including pharmacological and non-pharmacological approaches,offer systemic benefits for healthy aging.Intranasal brain-directed drug administration represents a promising avenue for effectively targeting specific brain regions,like the hypothalamus,while reducing side effects associated with systemic drug delivery,thereby presenting new therapeutic possibilities for diverse age-related conditions.

关键词： aging astrocytes cellular stress responses circadian clock hypothalamus intranasal drug administration metabolic control nutrient sensor SIRT1 sleep homeostasis

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Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma

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World Journal of Gastroenterology 2023年第17期29卷 2571-2599页

作者： Fernanda Villarruel-Melquiades María Eugenia Mendoza-Garrido Claudia M García-Cuellar yesennia Sánchez-Pérez Julio Isael Pérez-Carreón Javier Camacho departamento de Farmacología Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional(CINVESTAV-IPN)Mexico City 07360Mexico departamento de Fisiología Biofísica y NeurocienciasCentro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional(CINVESTAVIPN)Mexico City 07360Mexico Subdirección de investigación Básica Instituto Nacional de Cancerología(INCan)Mexico City 14080Mexico instituto nacional de Medicina Genómica Instituto Nacional de Medicina Genómica(INMEGEN)Mexico City 14610Mexico

Hepatocellular carcinoma(HCC)is one of the most lethal malignant tumours worldwide.The mortality-to-incidence ratio is up to 91.6%in many countries,representing the third leading cause of cancer-related deaths.Systemic drugs,including the multikinase inhibitors sorafenib and lenvatinib,are first-line drugs used in HCC treatment.Unfortunately,these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance.Thus,novel pharmacological alternatives are urgently needed.For instance,immune checkpoint inhibitors have provided new approaches targeting cells of the immune system.Furthermore,monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients.In addition,drug combinations,including first-line treatment and immunotherapy,as well as drug repurposing,are promising novel therapeutic alternatives.Here,we review the current and novel pharmacological approaches to fight HCC.Preclinical studies,as well as approved and ongoing clinical trials for liver cancer treatment,are discussed.The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.

关键词： Liver cancer Systemic therapy Immunotherapy Drug repurposing Drug combinations Hepatocellular carcinoma

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Surgical and nutritional interventions for endometrial receptivity:A case report and review of literature

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World Journal of Clinical Cases 2022年第33期10卷 12295-12304页

作者： Dinorah Hernández-Melchor Cecilia Palafox-Gómez Ivan Madrazo Ginna Ortiz America Padilla-Viveros Esther López-Bayghen Science Technology and Society ProgramCentro de Investigación y de Estudios Avanzados del Instituto Politécnico NacionalMéxico City 07360CDMXMéxico Clinical Research Instituto Regenera SCMéxico City 05320CDMXMéxico departamento de Toxicología Centro de Investigación y de Estudios Avanzados del Instituto Politécnico NacionalMéxico City 07360CDMXMéxico investigación Clínica Instituto de Infertilidad y Genética México SCINGENESMéxico City 05320CDMXMéxico departamento de Toxicología Centro de Investigación y de Estudios Avanzados del Instituto Politécnico NacionalMexico City 07360CDMXMéxico

BACKGROUnD Polycystic ovary syndrome(PCOS)is an endocrine disease that combines metabolic,reproductive,and psychological dysfunctions.Ovulation disorders and impaired endometrial receptivity in PCOS can cause infertility.Insulin resistance(IR)is a pathological state of inadequate response to insulin that affects reproduction in PCOS,as damage caused by IR at the endometrial level becomes an obstacle for embryo implantation.Reversing IR resulted in spontaneous pregnancies in PCOS patients,indicating that metabolic corrections improve endometrial dysfunctions.Mesenchymal stem-cell treatment has also corrected endometrial quality and lead to pregnancies in patients with Asherman’s syndrome.We propose a combination of nutritional intervention with the surgical placement of stem cells to improve endometrial quality to achieve pregnancy in a PCOS patient undergoing in vitro fertilization(IVF)treatment.CASE SUMMARy After two failed IVF cycles,a metabolic intervention,consisting of a ketogenic diet with daily consumption of 50 g of carbohydrates(CH),was indicated until pregnancy.Metabolic Syndrome was assessed using the Harmonizing definition(3 of 5 pathologies:Central obesity,hypertension,hyperglycemia,hypertriglyceridemia,and dyslipidemia),and the Homeostatic Model Assessment of IR(HOMA-IR)was used to measure the level of IR.Once IR improved,endometrial quality improved.However,two day 5-thawed embryos(euploid,donated oocyte–partner's sperm)failed to implant,suggesting endometrial quality improvement was insufficient.Therefore,transmyometrial implantation of mesenchymal stem cells from the stromal vascular fraction of adipose tissue was performed to enrich the endometrial stem cell niche.Minimal endometrial mean thickness for embryo transfer(6.9 mm)was achieved three months after stem cell treatment and continuous dietary control of IR.Two euploid-day 5-thawed embryos(donated oocyte–partner's sperm)were transferred,and embryo implantation was confirmed on day 14 byβ-hCG serum levels.Currently,a 37 wk baby girl is born.

关键词： Polycystic ovarian syndrome Insulin resistance nutritional intervention Endometrial quality Stem cell treatment Case report

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Cerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration

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neural Regeneration Research 2022年第4期17卷 854-866页

作者： Manuel A.Fernandez-Parrilla David Reyes-Corona yazmin M.Flores-Martinez Rasajna nadella Michael J.Bannon Lourdes Escobedo Minerva Maldonado-Berny Jaime Santoyo-Salazar Luis O.Soto-Rojas Claudia Luna-Herrera Jose Ayala-Davila Juan A.Gonzalez-Barrios Gonzalo Flores Maria E.Gutierrez-Castillo Armando JEspadas-Alvarez Irma A.Martínez-Dávila Porfirio nava Daniel Martinez-Fong departamento de Fisiología Biofísica y NeurocienciasCentro de Investigación y de Estudios AvanzadosCiudad de MéxicoMéxico Programa Institucional de Biomedicina Molecular Escuela Nacional de Medicina y HomeopatíaInstituto Politécnico NacionalCiudad de MéxicoMéxico department of Biosciences IIIT-SrikakulamRajiv Gandhi University of Knowledge Technologies(RGUKT)Andhra PradeshIndia department of Pharmacology Wayne State University School of MedicineDetroitMIUSA departamento de Física Centro de Investigación y de Estudios AvanzadosCiudad de MéxicoMéxico Facultad de estudios Superiores Iztacala Universidad Nacional Autónoma de MéxicoTlalnepantla de BazEdo.de MéxicoMéxico departamento de Fisiología Escuela Nacional de Ciencias BiológicasCiudad de MéxicoMéxico Laboratorio de Medicina Genómica Hospital Regional“1°de Octubre”ISSSTECiudad de MéxicoMéxico Laboratorio de neuropsiquiatría Instituto de FisiologíaBenemérita Universidad Autónoma de PueblaPueblaPueblaMéxico departamento de Biociencias e Ingeniería Centro Interdisciplinario de Investigaciones y Estudios sobre Medio Ambiente y DesarrolloInstituto Politécnico NacionalCiudad de MéxicoMéxico Programa de nanociencias y nanotecnología Centro de Investigación y de Estudios AvanzadosCiudad de MéxicoMéxico

Overexpression of neurotrophic factors in nigral dopamine neurons is a promising approach to reverse neurodegeneration of the nigrostriatal dopamine system,a hallmark in Parkinson's disease.The human cerebral dopamine neurotrophic factor(h CDnF)has recently emerged as a strong candidate for Parkinson's disease therapy.This study shows that h CDnF expression in dopamine neurons using the neurotensinpolyplex nanoparticle system reverses 6-hydroxydopamine-induced morphological,biochemical,and behavioral alterations.Three independent electron microscopy techniques showed that the neurotensin-polyplex nanoparticles containing the h CDnF gene,ranging in size from 20 to 150 nm,enabled the expression of a secretable h CDnF in vitro.Their injection in the substantia nigra compacta on day 21 after the 6-hydroxydopamine lesion resulted in detectable h CDnF in dopamine neurons,whose levels remained constant throughout the study in the substantia nigra compacta and striatum.Compared with the lesioned group,tyrosine hydroxylase-positive(TH^(+))nigral cell population and TH+fiber density rose in the substantia nigra compacta and striatum after h CDnF transfection.An increase inβIII-tubulin and growth-associated protein 43 phospho-S41(GAP43 p)followed TH^(+)cell recovery,as well as dopamine and its catabolite levels.Partial reversal(80%)of drugactivated circling behavior and full recovery of spontaneous motor and non-motor behavior were achieved.Brain-derived neurotrophic factor recovery in dopamine neurons that also occurred suggests its participation in the neurotrophic effects.These findings support the potential of nanoparticle-mediated h CDnF gene delivery to develop a disease-modifying treatment against Parkinson's disease.The Institutional Animal Care and Use Committee of centro de investigación y de estudios avanzados approved our experimental procedures for animal use(authorization no.162-15)on June 9,2019.

关键词： axonal growth brain-derived neurotrophic factor gene delivery nanoparticles neuritogenesis neuronal cytoskeleton neuroregeneration neurorestoration neurotrophic therapy Parkinson's disease reinnervation substantia nigra

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Review: neuronal Differentiation Protocols of Mesenchymal Stem Cells

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Advances in Bioscience and Biotechnology 2022年第1期13卷 15-71页

作者： Miguel A. Jiménez-Acosta Lory Jhenifer Rochín Hernández Mayte Lizeth Padilla Cristerna José Tapia-Ramírez Marco A. Meraz-Ríos department of Molecular Biomedicine Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional Instituto Politécnico Nacional México City México department of Genetic and Molecular Biology Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional Instituto Politécnico Nacional México City México

Mesenchymal stem cells (MSCs) are self-renewing cells found in almost all postnatal organs and tissues in the perivascular region. These cells present multiple characteristics that make them candidates to be applied in cell therapy for neurodegenerative diseases, such as their secretory action, migration to the lesion area, and immunomodulatory potential. These cells have a high capacity for mesodermal differentiation;however, numerous studies have shown that MSCs can also differentiate into neurons. However, despite positive results in multiple trials in which undifferentiated MSCs transplanted into animal models of neurodegenerative diseases, some studies suggest that the therapeutic effects obtained are enhanced by the use of MSCs differentiated towards the neuronal lineage before transplant. In this sense, there are several methods to induce in vitro reprogramming of MSCs towards the neuronal lineage, including chemical substances, growth factors, cocultures with neural lineage cells, transfection of genes, miRnAs, etc., and small molecules stand out. Therefore, this article compares multiple experimental tests in which these inducers promote neuronal differentiation of MSCs and identify those methods that originate an optimal neuronal differentiation. The analysis includes the percentage of differentiation, maturation, expression of neuronal markers, functionality, and cell survival considering the intrinsic characteristics of the MSCs used as the tissue of origin and the species from which they were isolated.

关键词： Mesenchymal Stem Cells Transdifferentiating neuronal Differentiation Small Molecules miRnA neural Induction

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Tale of two kinases:Protein kinase A and Ca^(2+)/calmodulin-dependent protein kinase Ⅱ in pre-diabetic cardiomyopathy

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World Journal of Diabetes 2021年第10期12卷 1704-1718页

作者： Pamela Gaitán-González Rommel Sánchez-Hernández José-Antonio Arias-Montaño Angélica Rueda department of Biochemistry Centro de Investigación y de Estudios Avanzados del Instituto Politécnico NacionalCiudad de México 07360Mexico department of Physiology Biophysics and NeurosciencesCentro de Investigación y de Estudios Avanzados del Instituto Politécnico NacionalCiudad de México 07360Mexico

Metabolic syndrome is a pre-diabetic state characterized by several biochemical and physiological alterations,including insulin resistance,visceral fat accumulation,and dyslipidemias,which increase the risk for developing cardiovascular disease.Metabolic syndrome is associated with augmented sympathetic tone,which could account for the etiology of pre-diabetic cardiomyopathy.This review summarizes the current knowledge of the pathophysiological consequences of enhanced and sustainedβ-adrenergic response in pre-diabetes,focusing on cardiac dysfunction reported in diet-induced experimental models of pre-diabetic cardiomyopathy.The research reviewed indicates that both protein kinase A and Ca^(2+)/calmodulin-dependent protein kinase Ⅱ play important roles in functional responses mediated byβ1-adrenoceptors;therefore,alterations in the expression or function of these kinases can be deleterious.This review also outlines recent information on the role of protein kinase A and Ca^(2+)/calmodulin-dependent protein kinase Ⅱ in abnormal Ca^(2+)handling by cardiomyocytes from diet-induced models of pre-diabetic cardiomyopathy.

关键词： Ca^(2+)/calmodulin-dependent protein kinase II Protein kinase A Metabolic syndrome Pre-diabetes Pre-diabetic cardiomyopathy β-Adrenoceptors

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road to stemness in hepatocellular carcinoma

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World Journal of Gastroenterology 2017年第37期23卷 6750-6776页

作者： Teresita nJ Flores-Téllez Saúl Villa-Trevino Carolina Pina-Vázquez departam ento de Biología Celular Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional(CINVESTAV-IPN) Av.IPN No.2508 Col

Carcinogenic process has been proposed to relay on the capacity to induce local tissue damage and proliferative repair. Liver has a great regeneration capacity and currently, most studies point towards the dominant role of hepatocytes in regeneration at all levels of liver damage. The most frequent liver cancer is hepatocellular carcinoma(HCC). Historical findings originally led to the idea that the cell of origin of HCC might be a progenitor cell. However, current linage tracing studies put the progenitor hypothesis of HCC origin into question. In agreement with their dominant role in liver regeneration, mature hepatocytes are emerging as the cell of origin of HCC, although, the specific hepatocyte subpopulation of origin is yet to be determined. The relationship between the cancer cell of origin(CCO) and cancer-propagating cells, known as hepatic cancer stem cell(HCSC) is unknown. It has been challenging to identify the definitive phenotypic marker of HCSC, probably due to the existence of different cancer stem cells(CSC) subpopulations with different functions within HCC. There is a dynamic interconversion among different CSCs, and between CSC and non-CSCs. Because of that, CSC-state is currently defined as a description of a highly adaptable and dynamic intrinsic property of tumor cells, instead of a static subpopulation of a tumor. Altered conditions could trigger the gain of stemness, some of them include: EMT-MET, epigenetics, microenvironment and selective stimulus such as chemotherapy. This CSC heterogeneity and dynamism makes them out reach from therapeutic protocols directed to a single target. A further avenue of research in this line will be to uncover mechanisms that trigger this interconversion of cell populations within tumors and target it.

关键词： Cancer stem cell Liver progenitor cell Liver stem progenitor cell Stemness Plasticity Cancer cell of origin Cancer stem cells subpopulations

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