Proinflammatory phenotype of iPS cell-derived JAK2 V617F megakaryocytes induces fibrosis in 3D in vitro bone marrow niche

The myeloproliferative disease polycythemia vera (PV) driven by the JAK2 V617F mutation can transform into myelofibrosis (post-PV-MF). It remains an open question how JAK2 V617F in hematopoietic stem cells induces MF. Megakaryocytes are major players in murine PV models but are difficult to study in the human setting. We generated induced pluripotent stem cells (iPSCs) from JAK2 V617F PV patients and differentiated them into megakaryocytes. In differentiation assays, JAK2 V617F iPSCs recapitulated the pathognomonic skewed megakaryocytic and erythroid differentiation. JAK2 V617F iPSCs had a TPO-independent and increased propensity to differentiate into megakaryocytes. RNA sequencing of JAK2 V617F iPSC-derived megakaryocytes reflected a proinflammatory, profibrotic phenotype and decreased ribosome biogenesis. In three-dimensional (3D) coculture, JAK2 V617F megakaryocytes induced a profibrotic phenotype through direct cell contact, which was reversed by the JAK2 inhibitor ruxolitinib. The 3D coculture system opens the perspective for further disease modeling and drug discovery.</p

The clash of Langerhans cell homeostasis in skin : Should I stay or should I go?

AbstractLangerhans cells (LC), the skin epidermal contingent of dendritic cells (DC), possess an exceptional life cycle and developmental origin. LC, like all mature blood cells, develop from haematopoietic stem cells (HSC) through successive steps of lineage commitment and differentiation. However, LC development is different to that of other DC subsets and not yet fully understood. Haematopoietic cell fate decisions are instructed by specific growth factors and cytokines produced in specialized microenvironments or niches. Upon ligand binding the cognate surface receptors on HSC and further restricted progenitor cells regulate the signalling pathways that eventually leads to the execution of lineage-determining genetic programs. In this review we focus on a specific set of surface receptor kinases that have been identified as critical regulators of LC development using genetically modified mice. Recent studies suggest for some of these kinases to impact on LC/LC progenitor interaction with the local niche by regulating adhesion and/or migration. During embryonic development, in wound healing and aberrantly in tumour invasion the same kinase receptors control a genetic program known as epithelial-to-mesenchymal-transition (EMT). We will discuss how EMT and its reverse program of mesenchymal-to-epithelial-transition (MET) can serve as universal concepts operating also in LC development

За кадры. 1999. № 11 (3011)

И кто придумал сдавать сессию летом?Цифры и факты / С. Дараева11 мая, в день 103-летия ТПУ, состоялся торжественный Ученый Совет, посвященный Дню УниверситетаПесня всех объединила / С. ФедоровНовости политехнического. Мы уже сообщали[Совет ветеранов] / А. В. АстафуровПолитехническому отдано 36 лет / В. Ф. КуцепаленкоНовости политехнического. Весной 1999 года / Е. В. АрляповаНовости политехнического. Итоги нового общеуниверситетского конкурса / Л. М. ЗольниковаНовости политехнического. Уважаемые товарищи! / Г. С. Бухановская, И. Н. Савельева, Е. И. АлибасоваНовости политехнического. Три дня в ТПУНовости политехнического. В числе пяти проектовМеждународное сотрудничествоСильный помогает слабому / С. МазуровГород вздрогнул... / Я. АнечкинаНе успевает тот, кто не торопится / Е. ЕфстифееваКогда изучать экологию? / Е. Т. ПротасевичГазовый факел озарил всю область / [беседа с] С. А. ЖвачкинОгни общежитий. Смотр-конкурсОгни общежитий. Мойдодыры политехническогоОгни общежитий. Праздник немецкой культуры в Томске / А. А. ФрицлерЭто сильно / И. ЮневаВыбор между жизнью и смертью - за вами!"Полигон" - чемпион!" / В. Прибаукин"Друзья, прекрасен наш союз!" / П. Веников"Нужно самим работать.." / И. БасалаеваКоролевские призерыСпартакиада есть! Спартакиада будет! / Б. Л. БайгуловПраздник, посвященный 103-летию ТПУ / А. СидороffВаш пропуск в XXI век200-летие поэта - достойный повод для "открытий чудных" / Л. И. ВласоваДядь, дай семьдесят копеек! / А. ГригорьевОбратная связ

Dendritic cell lineage commitment is instructed by distinct cytokine signals

AbstractDendritic cells (DC) develop from hematopoietic stem cells, which is guided by instructive signals through cytokines. DC development progresses from multipotent progenitors (MPP) via common DC progenitors (CDP) into DC. Flt3 ligand (Flt3L) signaling via the Flt3/Stat3 pathway is of pivotal importance for DC development under steady state conditions. Additional factors produced during steady state or inflammation, such as TGF-β1 or GM-CSF, also influence the differentiation potential of MPP and CDP. Here, we studied how gp130, GM-CSF and TGF-β1 signaling influence DC lineage commitment from MPP to CDP and further into DC. We observed that activation of gp130 signaling promotes expansion of MPP. Additionally, gp130 signaling inhibited Flt3L-driven DC differentiation, but had little effect on GM-CSF-driven DC development. The inflammatory cytokine GM-CSF induces differentiation of MPP into inflammatory DC and blocks steady state DC development. Global transcriptome analysis revealed a GM-CSF-driven gene expression repertoire that primes MPP for differentiation into inflammatory DC. Finally, TGF-β1 induces expression of DC-lineage affiliated genes in MPP, including Flt3, Irf-4 and Irf-8. Under inflammatory conditions, however, the effect of TGF-β1 is altered: Flt3 is not upregulated, indicating that an inflammatory environment inhibits steady state DC development. Altogether, our data indicate that distinct cytokine signals produced during steady state or inflammation have a different outcome on DC lineage commitment and differentiation