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1.
BMC Cancer ; 22(1): 476, 2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35490227

RESUMO

BACKGROUND: Prognostic indicators, treatments, and survival estimates vary by cancer type. Therefore, disease-specific models are needed to estimate patient survival. Our primary aim was to develop models to estimate survival duration after treatment for skeletal-related events (SREs) (symptomatic bone metastasis, including impending or actual pathologic fractures) in men with metastatic bone disease due to prostate cancer. Such disease-specific models could be added to the PATHFx clinical-decision support tool, which is available worldwide, free of charge. Our secondary aim was to determine disease-specific factors that should be included in an international cancer registry. METHODS: We analyzed records of 438 men with metastatic prostate cancer who sustained SREs that required treatment with radiotherapy or surgery from 1989-2017. We developed and validated 6 models for 1-, 2-, 3-, 4-, 5-, and 10-year survival after treatment. Model performance was evaluated using calibration analysis, Brier scores, area under the receiver operator characteristic curve (AUC), and decision curve analysis to determine the models' clinical utility. We characterized the magnitude and direction of model features. RESULTS: The models exhibited acceptable calibration, accuracy (Brier scores < 0.20), and classification ability (AUCs > 0.73). Decision curve analysis determined that all 6 models were suitable for clinical use. The order of feature importance was distinct for each model. In all models, 3 factors were positively associated with survival duration: younger age at metastasis diagnosis, proximal prostate-specific antigen (PSA) < 10 ng/mL, and slow-rising alkaline phosphatase velocity (APV). CONCLUSIONS: We developed models that estimate survival duration in patients with metastatic bone disease due to prostate cancer. These models require external validation but should meanwhile be included in the PATHFx tool. PSA and APV data should be recorded in an international cancer registry.


Assuntos
Neoplasias Ósseas , Neoplasias da Próstata , Algoritmos , Fosfatase Alcalina , Neoplasias Ósseas/secundário , Humanos , Aprendizado de Máquina , Masculino , Antígeno Prostático Específico , Neoplasias da Próstata/terapia
2.
J Urol ; 206(3): 623-629, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34003011

RESUMO

PURPOSE: There were 3 recent U.S. Food and Drug Administration approvals for drugs to be used in nonmetastatic castration resistant prostate cancer, a state that arises from the unproven start of continuous androgen deprivation therapy (ADT) for biochemical recurrent prostate cancer (BCR), before metastatic disease is evident. This report examines the outcome of men with BCR who defer ADT until time of metastasis. MATERIALS AND METHODS: Retrospective review of men diagnosed with clinically localized prostate cancer who underwent radical prostatectomy at Johns Hopkins Hospital and Walter Reed National Military Medical Center and developed BCR with a prostate specific antigen doubling time of not more than 10 months (806 patients). The primary end points were metastasis-free survival and overall survival from time of local treatment among men who delayed ADT until time of metastasis. RESULTS: The median metastasis-free survival of men with BCR and a prostate specific antigen doubling time <6 months and 10 months who delay ADT until metastasis is 144 months (95% CI 48-not reached) and 192 months (95% CI 72-not reached), respectively, with a median overall survival of 168 months (95% CI 96-276 months) and 204 months (95% CI 120-276), respectively. CONCLUSIONS: Metastasis-free survival and overall survival of men with BCR who delay hormone therapy is long. This underscores the need to reevaluate when to start primary ADT in this patient population.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Calicreínas/sangue , Recidiva Local de Neoplasia/tratamento farmacológico , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/terapia , Tempo para o Tratamento/estatística & dados numéricos , Idoso , Quimioterapia Adjuvante/métodos , Tomada de Decisão Clínica , Progressão da Doença , Intervalo Livre de Doença , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Guias de Prática Clínica como Assunto , Próstata/patologia , Próstata/cirurgia , Prostatectomia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/mortalidade , Estudos Retrospectivos , Fatores de Tempo , Tempo para o Tratamento/normas
3.
J Exp Biol ; 220(Pt 2): 294-303, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27811293

RESUMO

Rhodopsin (rh1) is the visual pigment expressed in rod photoreceptors of vertebrates that is responsible for initiating the critical first step of dim-light vision. Rhodopsin is usually a single copy gene; however, we previously discovered a novel rhodopsin-like gene expressed in the zebrafish retina, rh1-2, which we identified as a functional photosensitive pigment that binds 11-cis retinal and activates in response to light. Here, we localized expression of rh1-2 in the zebrafish retina to a subset of peripheral photoreceptor cells, which indicates a partially overlapping expression pattern with rh1 We also expressed, purified and characterized Rh1-2, including investigation of the stability of the biologically active intermediate. Using fluorescence spectroscopy, we found the half-life of the rate of retinal release of Rh1-2 following photoactivation to be more similar to that of the visual pigment rhodopsin than to the non-visual pigment exo-rhodopsin (exorh), which releases retinal around 5 times faster. Phylogenetic and molecular evolutionary analyses show that rh1-2 has ancient origins within teleost fishes, is under similar selective pressure to rh1, and likely experienced a burst of positive selection following its duplication and divergence from rh1 These findings indicate that rh1-2 is another functional visual rhodopsin gene, which contradicts the prevailing notion that visual rhodopsin is primarily found as a single copy gene within ray-finned fishes. The reasons for retention of this duplicate gene, as well as possible functional consequences for the visual system, are discussed.


Assuntos
Rodopsina/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Evolução Molecular , Filogenia , Pigmentos da Retina , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Rodopsina/metabolismo , Análise de Sequência de DNA , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
4.
Dev Biol ; 373(1): 95-106, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23103586

RESUMO

Bone morphogenetic proteins (BMPs) are involved in embryonic mammary gland (MG) development and can be dysregulated in breast cancer. However, the role BMPs play in the postnatal MG remains virtually unknown. BMPs are potent morphogens that are involved in cell fate determination, proliferation, apoptosis and adult tissue homeostasis. Twisted gastrulation (TWSG1) is a secreted BMP binding protein that modulates BMP ligand availability in the extracellular space. Here we investigate the consequences of TWSG1 deletion on development of the postnatal MG. At puberty, Twsg1 is expressed in the myoepithelium and in a subset of body cells of the terminal end buds. In the mature duct, Twsg1 expression is primarily restricted to the myoepithelial layer. Global deletion of Twsg1 leads to a delay in ductal elongation, reduced secondary branching, enlarged terminal end buds, and occluded lumens. This is associated with an increase in luminal epithelial cell number and a decrease in apoptosis. In the MG, pSMAD1/5/8 level and the expression of BMP target genes are reduced, consistent with a decrease in BMP signaling. GATA-3, which is required for luminal identity, is reduced in Twsg1(-/-) MGs, which may explain why K14 positive cells, which are normally restricted to the myoepithelial layer, are found within the luminal compartment and shed into the lumen. In summary, regulation of BMP signaling by TWSG1 is required for normal ductal elongation, branching of the ductal tree, lumen formation, and myoepithelial compartmentalization in the postnatal MG.


Assuntos
Proteínas Morfogenéticas Ósseas/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Glândulas Mamárias Animais/crescimento & desenvolvimento , Proteínas/metabolismo , Transdução de Sinais/fisiologia , Animais , Apoptose/fisiologia , Western Blotting , Bromodesoxiuridina , Linhagem Celular , Proliferação de Células , Epitélio/metabolismo , Feminino , Galactosídeos , Regulação da Expressão Gênica no Desenvolvimento/genética , Técnicas de Introdução de Genes , Hematoxilina , Imuno-Histoquímica , Indóis , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/transplante , Camundongos , Camundongos Knockout , Proteínas/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
NPJ Precis Oncol ; 8(1): 208, 2024 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-39294262

RESUMO

We analyzed genomic data from the prostate cancer of African- and European American men to identify differences contributing to racial disparity of outcome. We also performed FISH-based studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate cancer tissue microarrays. We created CHD1-deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. Subclonal deletion of CHD1 was nearly three times as frequent in prostate tumors of African American than in European American men and it associates with rapid disease progression. CHD1 deletion was not associated with HR deficiency associated mutational signatures or HR deficiency as detected by RAD51 foci formation. This was consistent with the moderate increase of olaparib and talazoparib sensitivity with several CHD1 deficient cell lines showing talazoparib sensitivity in the clinically relevant concentration range. CHD1 loss may contribute to worse disease outcome in African American men.

6.
Res Sq ; 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38645014

RESUMO

We analyzed genomic data derived from the prostate cancer of African and European American men in order to identify differences that may contribute to racial disparity of outcome and that could also define novel therapeutic strategies. In addition to analyzing patient derived next generation sequencing data, we performed FISH based confirmatory studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate cancer tissue microarrays. We created CRISPR edited, CHD1 deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. We found that subclonal deletion of CHD1 is nearly three times as frequent in prostate tumors of African American men than in men of European ancestry and it associates with rapid disease progression. We further showed that CHD1 deletion is not associated with homologous recombination deficiency associated mutational signatures in prostate cancer. In prostate cancer cell line models CHD1 deletion did not induce HR deficiency as detected by RAD51 foci formation assay or mutational signatures, which was consistent with the moderate increase of olaparib sensitivity. CHD1 deficient prostate cancer cells, however, showed higher sensitivity to talazoparib. CHD1 loss may contribute to worse outcome of prostate cancer in African American men. A deeper understanding of the interaction between CHD1 loss and PARP inhibitor sensitivity will be needed to determine the optimal use of targeted agents such as talazoparib in the context of castration resistant prostate cancer.

7.
Am J Trop Med Hyg ; 2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35189586

RESUMO

The Deployment and Travel Medicine Knowledge, Attitude, Practice and Outcomes Study investigates the various clinician and traveler contributions to medical outcomes within the U.S. Military Health System. Travelers' diarrhea is among the most common travel-related illnesses, making travelers' diarrhea self-treatment (TDST) important for traveler health. A cohort of 80,214 adult travelers receiving malaria chemoprophylaxis for less than 6 weeks of travel were identified within the U.S. Department of Defense Military Health System Data Repository. Associated prescriptions for TDST medications within 2 weeks of chemoprophylaxis prescriptions were identified. Prescription patterns were compared by service member versus beneficiary status and site of care, military facility versus civilian facility. At military facilities, medical provider demographics were analyzed by clinical specialty and categorized as travel medicine specialists versus nonspecialists. Overall, there was low prescribing of TDST, particularly among civilian providers and military nonspecialists, despite guidelines recommending self-treatment of moderate to severe travelers' diarrhea. This practice gap was largest among service member travelers, but also existed for beneficiaries. Compared with nonspecialists, military travel medicine specialists were more likely to prescribe a combination of an antibiotic and antimotility agent to beneficiaries, more likely to provide any form of TDST to service members, and more likely to prescribe azithromycin than quinolones when using antibiotics. Our study suggests that enhancing provider knowledge and use of travelers' diarrhea treatment recommendations combined with improved access to formal travel medicine services may be important to increase the quality of care.

8.
BMC Dev Biol ; 10: 100, 2010 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-20860823

RESUMO

BACKGROUND: The Dmbx1 gene is important for the development of the midbrain and hindbrain, and mouse gene targeting experiments reveal that this gene is required for mediating postnatal and adult feeding behaviours. A single Dmbx1 gene exists in terrestrial vertebrate genomes, while teleost genomes have at least two paralogs. We compared the loss of function of the zebrafish dmbx1a and dmbx1b genes in order to gain insight into the molecular mechanism by which dmbx1 regulates neurogenesis, and to begin to understand why these duplicate genes have been retained in the zebrafish genome. RESULTS: Using gene knockdown experiments we examined the function of the dmbx1 gene paralogs in zebrafish, dmbx1a and dmbx1b in regulating neurogenesis in the developing retina and midbrain. Dose-dependent loss of dmbx1a and dmbx1b function causes a significant reduction in growth of the midbrain and retina that is evident between 48-72 hpf. We show that this phenotype is not due to patterning defects or persistent cell death, but rather a deficit in progenitor cell cycle exit and differentiation. Analyses of the morphant retina or anterior hindbrain indicate that paralogous function is partially diverged since loss of dmbx1a is more severe than loss of dmbx1b. Molecular evolutionary analyses of the Dmbx1 genes suggest that while this gene family is conservative in its evolution, there was a dramatic change in selective constraint after the duplication event that gave rise to the dmbx1a and dmbx1b gene families in teleost fish, suggestive of positive selection. Interestingly, in contrast to zebrafish dmbx1a, over expression of the mouse Dmbx1 gene does not functionally compensate for the zebrafish dmbx1a knockdown phenotype, while over expression of the dmbx1b gene only partially compensates for the dmbx1a knockdown phenotype. CONCLUSION: Our data suggest that both zebrafish dmbx1a and dmbx1b genes are retained in the fish genome due to their requirement during midbrain and retinal neurogenesis, although their function is partially diverged. At the cellular level, Dmbx1 regulates cell cycle exit and differentiation of progenitor cells. The unexpected observation of putative post-duplication positive selection of teleost Dmbx1 genes, especially dmbx1a, and the differences in functionality between the mouse and zebrafish genes suggests that the teleost Dmbx1 genes may have evolved a diverged function in the regulation of neurogenesis.


Assuntos
Ciclo Celular/fisiologia , Diferenciação Celular/fisiologia , Mesencéfalo , Fatores de Transcrição Otx/genética , Isoformas de Proteínas/genética , Retina , Células-Tronco/fisiologia , Fatores de Transcrição/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra , Animais , Animais Geneticamente Modificados , Embrião não Mamífero/anatomia & histologia , Embrião não Mamífero/patologia , Embrião não Mamífero/fisiologia , Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Proteínas de Homeodomínio , Mesencéfalo/embriologia , Mesencéfalo/crescimento & desenvolvimento , Mesencéfalo/patologia , Camundongos , Neurogênese/fisiologia , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/metabolismo , Fatores de Transcrição Otx/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Retina/embriologia , Retina/crescimento & desenvolvimento , Retina/patologia , Células-Tronco/citologia , Fatores de Transcrição/metabolismo , Peixe-Zebra/anatomia & histologia , Peixe-Zebra/embriologia , Peixe-Zebra/crescimento & desenvolvimento , Proteínas de Peixe-Zebra/metabolismo
9.
Urol Oncol ; 38(10): 794.e1-794.e9, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32139288

RESUMO

INTRODUCTION: Combined radiotherapy and hormonal treatment are recommended for intermediate- and high-risk prostate cancer (CaP). This study compared the long-term effects on health-related quality of life (HRQoL) of intermediate- and high-risk CaP patients managed with radiation therapy (RT) with vs. without hormone therapy (HT). METHODS: Patients with intermediate- and high-risk CaP enrolled in the Center for Prostate Disease Research diagnosed from 2007 to 2017 were included. EPIC and SF-36 questionnaires were completed and HRQoL scores were compared for patients receiving RT vs. RT + HT at baseline (pretreatment), 6, 12, 24, 36, 48, and 60 months after CaP diagnosis. Longitudinal patterns of change in HRQoL were modeled using linear regression models, adjusting for baseline HRQoL, age at CaP diagnosis, race, comorbidities, National Comprehensive Cancer Network (NCCN) risk stratum, time to treatment, and follow-up time. RESULTS: Of 164 patients, 93 (56.7%) received RT alone and 71 (43.3%) received RT + HT. Both groups reported comparable baseline HRQoL. Patients receiving RT+HT were more likely to be NCCN high risk as compared to those receiving only RT. The RT + HT patients experienced worse sexual function, hormonal function, and hormonal bother than those who only received RT; however, HRQoL recovered over time for the RT + HT group. No significant differences were observed between groups in urinary and bowel domains or SF-36 mental and physical scores. CONCLUSION: Combined RT + HT treatment was associated with temporary lower scores in sexual and hormonal HRQoL compared with RT only. Intermediate- and high-risk CaP patients should be counseled about the possible declines in HRQoL associated with HT.


Assuntos
Antineoplásicos Hormonais/efeitos adversos , Quimiorradioterapia/efeitos adversos , Neoplasias da Próstata/terapia , Qualidade de Vida , Radioterapia de Intensidade Modulada/efeitos adversos , Idoso , Antagonistas de Androgênios/efeitos adversos , Quimiorradioterapia/métodos , Defecação/efeitos dos fármacos , Defecação/efeitos da radiação , Seguimentos , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Psicológicos , Estudos Prospectivos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/mortalidade , Neoplasias da Próstata/psicologia , Radioterapia de Intensidade Modulada/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , Autorrelato/estatística & dados numéricos , Comportamento Sexual/efeitos dos fármacos , Comportamento Sexual/psicologia , Comportamento Sexual/efeitos da radiação , Resultado do Tratamento , Micção/efeitos dos fármacos , Micção/efeitos da radiação
10.
Cancers (Basel) ; 12(5)2020 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-32429558

RESUMO

Although ~40% of screen-detected prostate cancers (PCa) are indolent, advanced-stage PCa is a lethal disease with 5-year survival rates around 29%. Identification of biomarkers for early detection of aggressive disease is a key challenge. Starting with 52 candidate biomarkers, selected from existing PCa genomics datasets and known PCa driver genes, we used targeted mass spectrometry to quantify proteins that significantly differed in primary tumors from PCa patients treated with radical prostatectomy (RP) across three study outcomes: (i) metastasis ≥1-year post-RP, (ii) biochemical recurrence ≥1-year post-RP, and (iii) no progression after ≥10 years post-RP. Sixteen proteins that differed significantly in an initial set of 105 samples were evaluated in the entire cohort (n = 338). A five-protein classifier which combined FOLH1, KLK3, TGFB1, SPARC, and CAMKK2 with existing clinical and pathological standard of care variables demonstrated significant improvement in predicting distant metastasis, achieving an area under the receiver-operating characteristic curve of 0.92 (0.86, 0.99, p = 0.001) and a negative predictive value of 92% in the training/testing analysis. This classifier has the potential to stratify patients based on risk of aggressive, metastatic PCa that will require early intervention compared to low risk patients who could be managed through active surveillance.

11.
Cancers (Basel) ; 11(12)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842254

RESUMO

Dysfunctions of androgen/TGF-ß signaling play important roles in prostate tumorigenesis. Prostate Transmembrane Protein Androgen Induced 1 (PMEPA1) inhibits androgen and TGF-ß signaling via a negative feedback loop. The loss of PMEPA1 confers resistance to androgen signaling inhibitors and promotes bone metastasis. Conflicting reports on the expression and biological functions of PMEPA1 in prostate and other cancers propelled us to investigate isoform specific functions in prostate cancer (PCa). One hundred and twenty laser capture micro-dissection matched normal prostate and prostate tumor tissues were analyzed for correlations between quantitative expression of PMEPA1 isoforms and clinical outcomes with Q-RT-PCR, and further validated with a The Cancer Genome Atlas (TCGA) RNA-Seq dataset of 499 PCa. Cell proliferation was assessed with cell counting, plating efficiency and soft agar assay in androgen responsive LNCaP and TGF-ß responsive PC3 cells. TGF-ß signaling was measured by SMAD dual-luciferase reporter assay. Higher PMEPA1-a mRNA levels indicated biochemical recurrence (p = 0.0183) and lower PMEPA1-b expression associated with metastasis (p = 0.0173). Further, lower PMEPA1-b and a higher ratio of PMEPA1-a vs. -b were correlated to higher Gleason scores and lower progression free survival rate (p < 0.01). TGF-ß-responsive PMEPA1-a promoted PCa cell growth, and androgen-responsive PMEPA1-b inhibited cancer cell proliferation. PMEPA1 isoforms -a and -b were shown to be promising candidate biomarkers indicating PCa aggressiveness including earlier biochemical relapse and lower disease specific life expectancy via interrupting androgen/TGF-ß signaling.

12.
Biomed Res Int ; 2018: 4727089, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30050933

RESUMO

INTRODUCTION: Metastasis prostate cancer (CaP) occurs in a small fraction of patients. Improved prognostication of disease progression is a critical challenge. This study examined alkaline phosphatase velocity (APV) in predicting distant metastasis-free survival (DMFS). MATERIALS AND METHODS: This retrospective cohort study examined CaP patients enrolled in the Center for Prostate Disease Research (CPDR) multicenter national database who underwent RP and experienced BCR (n=1783). BCR was defined as a PSA ≥ 0.2 ng/mL at ≥ 8 weeks post-RP, followed by at least one confirmatory PSA ≥ 0.2 ng/mL or initiation of salvage therapy. APV was computed as the slope of the linear regression line of all alkaline phosphatase (AP) values after BCR and prior to distant metastasis. APV values in the uppermost quartile were defined as "rapid" and compared to the lower three quartiles combined ("slower"). Unadjusted Kaplan Meier (KM) estimation curves and multivariable Cox proportional hazards analysis were used to examine predictors of DMFS. RESULTS: Of the 1783 eligible patients who experienced post-RP BCR, 701 (39.3%) had necessary AP data for APV calculation. PSA doubling time (PSADT) and APV were strongly associated (p=0.008). No differences in APV were observed across race. In KM analysis, significantly poorer DMFS was observed among the rapid versus slower APV group (Log-rank p=0.003). In multivariable analysis, a rapid APV was predictive of a twofold increased probability of DMFS (HR = 2.2; 95% CI = 1.2, 3.9; p = 0.008), controlling for key study covariates. CONCLUSIONS: Building on previous work, this study found that rapid APV was a strong predictor of DMFS for a broader group of CaP patients, those who undergo post-RP BCR who were enrolled in a longitudinal cohort with long-term follow-up and equal health care access. APV is worth considering as a complementary clinical factor for predicting DMFS.


Assuntos
Fosfatase Alcalina/metabolismo , Metástase Neoplásica , Neoplasias da Próstata/patologia , Idoso , Intervalo Livre de Doença , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Modelos de Riscos Proporcionais , Antígeno Prostático Específico , Prostatectomia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/cirurgia , Recidiva , Estudos Retrospectivos
13.
Stem Cells Dev ; 18(10): 1533-42, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19326969

RESUMO

Adult tissues are known to contain rare populations of stem cells with multilineage differentiation potential that are distinct from other resident tissue-specific stem cells. However, whether multilineage stem cells are involved in tissue development is uncertain, primarily because the identification and characterization of these cells in embryonic tissue primordia is not well established. We tested whether stem cells with multilineage potential are present within the early post-gastrula somite tissue. We show that clonally derived precursor cells generate colonies with self-renewal capacity and have both neurogenic and myogenic lineage potential. Somite colonies contain cells that express Sox2, nestin, and Sca1, but do not express genes indicative of somitic mesoderm specification. Furthermore, we demonstrate that this multilineage potential is not due to colony cells with a pluripotent epiblast identity or the selection of p75 receptor-positive neural crest stem cells. Despite utilizing a highly undifferentiated tissue source, colony formation was not enhanced relative to reported estimates of multilineage stem cells from adult muscle, a derivative of the embryonic somite. Thus, our findings suggest that a permissive in vitro environment is sufficient for the isolation of a discrete population of stem cells in the embryonic somite that may represent the earliest developmental precursor to adult muscle multilineage stem cells.


Assuntos
Separação Celular/métodos , Gástrula/citologia , Neurogênese , Somitos/citologia , Células-Tronco/citologia , Animais , Ataxina-1 , Ataxinas , Proliferação de Células , Células Cultivadas , Células Clonais , Ensaio de Unidades Formadoras de Colônias , Meios de Cultura Livres de Soro , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Gástrula/metabolismo , Mesoderma/citologia , Mesoderma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Desenvolvimento Muscular , Miocárdio/citologia , Miocárdio/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Proteínas Nucleares/metabolismo , Somitos/metabolismo , Células-Tronco/metabolismo
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