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1.
Stem Cells ; 35(3): 626-640, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28009074

RESUMO

The study and application of human pluripotent stem cells (hPSCs) will be enhanced by the availability of well-characterized monoclonal antibodies (mAbs) detecting cell-surface epitopes. Here, we report generation of seven new mAbs that detect cell surface proteins present on live and fixed human ES cells (hESCs) and human iPS cells (hiPSCs), confirming our previous prediction that these proteins were present on the cell surface of hPSCs. The mAbs all show a high correlation with POU5F1 (OCT4) expression and other hPSC surface markers (TRA-160 and SSEA-4) in hPSC cultures and detect rare OCT4 positive cells in differentiated cell cultures. These mAbs are immunoreactive to cell surface protein epitopes on both primed and naive state hPSCs, providing useful research tools to investigate the cellular mechanisms underlying human pluripotency and states of cellular reprogramming. In addition, we report that subsets of the seven new mAbs are also immunoreactive to human bone marrow-derived mesenchymal stem cells (MSCs), normal human breast subsets and both normal and tumorigenic colorectal cell populations. The mAbs reported here should accelerate the investigation of the nature of pluripotency, and enable development of robust cell separation and tracing technologies to enrich or deplete for hPSCs and other human stem and somatic cell types. Stem Cells 2017;35:626-640.


Assuntos
Anticorpos Monoclonais/imunologia , Proteínas de Membrana/imunologia , Células-Tronco Pluripotentes/metabolismo , Animais , Antígenos de Superfície/metabolismo , Técnicas de Cultura de Células , Diferenciação Celular , Autorrenovação Celular , Regulação para Baixo/genética , Corpos Embrioides/citologia , Corpos Embrioides/metabolismo , Citometria de Fluxo , Células-Tronco Hematopoéticas/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Fator 3 de Transcrição de Octâmero/metabolismo
2.
J Autoimmun ; 70: 40-51, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27055778

RESUMO

Fingolimod, an oral therapeutic agent approved for patients with relapsing-remitting Multiple Sclerosis (MS), has been shown to prevent lymphocyte egress from secondary lymphoid tissues; however the specific drug effect on B cells in fingolimod-treated patients remains to be fully elucidated. We present here a comprehensive analysis on the proportions of B cell subsets in the periphery, and the levels of activation, functional surface markers and cytokine profile of B cells in MS patients, following initiation of fingolimod therapy, using flow cytometry and cytokine bead array. Fingolimod therapy increased the ratio of naïve to memory cells, elevated the percentage of plasma cells and highly increased the proportion of transitional B cells as well as additional regulatory subsets, including: IL10(+), CD25(+) and CD5(+) B cells. The percentage of activated CD69(+) cells was highly elevated in the remaining circulating B cells, which produced increased levels of IL10, TGFß, IL6, IL4, LTα, TNFα and IFNγ cytokines, with an overall increased ratio of TGFß to pro-inflammatory cytokines. Furthermore, fingolimod therapy reduced ICAM-1(+) cells, suggesting a possible reduction in antigen-presenting capacity. Phosphorylated-fingolimod was shown in vitro to reduce S1PR1 RNA and protein, to slightly increase viability and to activate anti-apoptotic Bcl2 in transformed B cells of patients with MS. In conclusion, fingolimod therapy modulates significantly the composition of circulating B cells, promoting regulatory subsets and an anti-inflammatory cytokine repertoire.


Assuntos
Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Interleucina-10/biossíntese , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Fator de Crescimento Transformador beta/biossíntese , Adulto , Apresentação de Antígeno/imunologia , Subpopulações de Linfócitos B/citologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Citocinas/metabolismo , Feminino , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Expressão Gênica , Humanos , Memória Imunológica , Imunofenotipagem , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Mediadores da Inflamação/metabolismo , Contagem de Leucócitos , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Plasmócitos/imunologia , Plasmócitos/metabolismo , Receptores de Lisoesfingolipídeo/genética , Receptores de Lisoesfingolipídeo/metabolismo , Receptores de Esfingosina-1-Fosfato , Adulto Jovem
3.
Am J Physiol Gastrointest Liver Physiol ; 302(11): G1274-81, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22461028

RESUMO

Numerous cytokines have been shown to affect epithelial cell differentiation and proliferation through epithelial-mesenchymal interaction. Growing evidence suggests that platelet-derived growth factor (PDGF) signaling is an important mediator of these interactions. The purpose of this study was to evaluate the effect of PDGF-α on enterocyte turnover in a rat model of short bowel syndrome (SBS). Male rats were divided into four groups: Sham rats underwent bowel transection, Sham-PDGF-α rats underwent bowel transection and were treated with PDGF-α, SBS rats underwent a 75% bowel resection, and SBS-PDGF-α rats underwent bowel resection and were treated with PDGF-α. Parameters of intestinal adaptation, enterocyte proliferation and apoptosis were determined at euthanasia. Illumina's Digital Gene Expression analysis was used to determine PDGF-related gene expression profiling. PDGF-α and PDGF-α receptor (PDGFR-α) expression was determined by real-time PCR. Western blotting was used to determine p-ERK, Akt1/2/3, bax, and bcl-2 protein levels. SBS rats demonstrated a significant increase in PDGF-α and PDGFR-α expression in jejunum and ileum compared with sham animals. SBS-PDGF-α rats demonstrated a significant increase in bowel and mucosal weight, villus height, and crypt depth in jejunum and ileum compared with SBS animals. PDGF-α receptor expression in crypts increased in SBS rats (vs. sham) and was accompanied by an increased cell proliferation following PDGF-α administration. A significant decrease in cell apoptosis in this group was correlated with lower bax protein levels. In conclusion, in a rat model of SBS, PDGF-α stimulates enterocyte turnover, which is correlated with upregulated PDGF-α receptor expression in the remaining small intestine.


Assuntos
Proliferação de Células/efeitos dos fármacos , Enterócitos/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Fator de Crescimento Derivado de Plaquetas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Enterócitos/metabolismo , Expressão Gênica , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Intestino Delgado/cirurgia , Masculino , Ratos , Ratos Sprague-Dawley , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Síndrome do Intestino Curto/genética , Síndrome do Intestino Curto/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
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