RESUMO
In the adult, hematopoietic stem cells (HSCs) are resident in the bone marrow (BM) compartment and are in direct association with the BM stromal microenvironment. However, human adult HSCs are largely quiescent and undergo limited self-renewal. This is in contrast to the higher frequency of cycling HSCs undergoing self-renewal during fetal development when hematopoiesis is transiently localized to the fetal liver (FL), suggesting that FL provides a more conducive microenvironment to support HSCs. Here, we provide phenotypic and molecular characterization of primary human FL stromal cells capable of supporting human repopulating progenitors. Qualitative and quantitative analysis revealed several properties unique to FL stromal cells compared to adult BM-derived stroma that included a greater than 10-fold enhanced proliferative capacity of FL stromal vs adult BM, and a 2-fold increase in the number of N-cadherin- and osteopontin-expressing cells. Supportive of extrinsic influences likely to modulate HSC expansion, global gene expression microarray analysis revealed that FL stroma has higher expression of regulators of the Wnt signaling pathway compared to adult BM stroma, which demonstrated an increased expression of the Notch signaling pathway. Our results suggest that human FL stromal cells provide a unique microenvironment to HSCs compared to adult BM stroma by controlling Wnt signaling of HSCs during human fetal hematopoietic development, while Notch signaling is tightly regulated by the HSC microenvironment in the adult. We propose that the human HSC niche is ontogenically controlled during human development to provide appropriate expansion of fetal HSCs and subsequent maintenance of adult HSCs.
Assuntos
Feto/anatomia & histologia , Células-Tronco Hematopoéticas , Fígado , Células Estromais/fisiologia , Adulto , Animais , Células Cultivadas , Técnicas de Cocultura , Feminino , Feto/fisiologia , Perfilação da Expressão Gênica , Idade Gestacional , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Humanos , Fígado/citologia , Fígado/fisiologia , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , Receptores Notch/genética , Receptores Notch/metabolismo , Transdução de Sinais/fisiologia , Transplante de Células-Tronco , Células Estromais/citologia , Proteínas Wnt/genética , Proteínas Wnt/metabolismoRESUMO
Pathology training programs typically retain teaching files of classic and unusual diagnostic cases. Since diagnostic criteria and terminology are mutable, we reviewed a surgical pathology teaching archive to determine if the materials continued to be acceptable for educational purposes. Each case (from 2001-2003) consisted of 1 to 3 slides and a 3 x 5 card with clinical information and the diagnosis. Cases were reviewed at a daily faculty consensus conference and categorized as follows: no diagnostic change; diagnosis added; or changed diagnosis. Slides were entirely missing from 79 (35.0%) of the 226 cases reviewed. Of the remaining 147 cases, 28 (19.0%) required additional clinical information and/or slides. The final disposition of the 147 cases was as follows: diagnosis unchanged, 126 (85.7%); diagnosis added, 15 (10.2%); and diagnosis changed, 6 (4.1%). Teaching files should be subject to prospective and retrospective controls to preserve the quality of the educational experience.