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Когда стволовые клетки делятся, то они генерируют потомство с тем же самым потенциалом развития, что и оригинальные клетки, этот процесс наз. само-обновлением. Самообновление управляется от природы экспрессией генов зависимым от типа клеток образом и модулируется за счет взаимодействий с внешними сигналами из окружающей среды, такими как факторы роста. Однако, несмотря на распространенность термина самообновления в научно литературе, этот процесс не определен на молекулярном уровне. Гематопоэтические стволовые клетки представляют собой прекрасную модель для изучения самообновления, т.к. они могут быть выделены, ими относительно легко манипулировать и они могут быть оценены с помощью хорошо известных методов. Установление принципов самообновления у гематопоэтических стволовых клеток д. пролить свет на механизмы сомообновления в др. тканях.
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Box 1 Conserved aspects of HSC self-renewal
The biological properties and activities that are involved in the self-renewal of HSCs are detailed below.
Self-renewal occurs autonomously in HSCs and is also affected by the environment (or stem-cell niche).
Self-renewal is activated by diverse signals, such as developmental regulators or certain oncogenes. The diversity of signals might make this process robust, in that a single signalling pathway is not the sole mediator. For example, Мус, NOTCH and leukaemic fusion proteins stimulate self-renewal53,96, so signalling through multiple pathways is likely to trigger a set of cellular events associated with self-renewal.
Some of the pathways used during embryogenesis are used during adult HSC self-renewal. These include signalling pathways mediated by Delta-like, WNT proteins, BMPs, fibroblast growth factors, retinoic acid and PGE2. Some factors are required for the production of HSCs during embryogenesis but are not required for the self-renewal of HSCs at later developmental stages: for example, the transcription factors SCL and RUNX1 (ref. 93).
HSCs do not seem to require the developmental regulators for adult stem-cell homeostasis. Conditional gene knockouts in mice have shown that developmental factors such as WNT proteins and NOTCH are not usually involved in HSC maintenance but are involved in stress-induced situations or during regeneration97,98.
Most of the developmental pathways involved in self-renewal are conserved in many tissues and in many organisms.
Self-renewal is linked to the cell cycle. The chromatin-associated factor ВМИ has been implicated in the self-renewal programme, and it directly regulates the transcription of the cell-cycle regulator INK4A99,100.
Self-renewal is activated quickly. An example of this is that the transformation event in cancer cells spontaneously and rapidly activates self-renewal.
Self-renewal can be augmented in stem cells that are already capable of self-renewal. HSCs can execute the self-renewal programme, but the addition of WNT3A24, angiopoietin-like factors75 or PGE2 (ref. 56) to the cells can increase the number of cells that engraft after transplantation. Most of the signalling pathways that are involved in self-renewal are not maximally stimulated in vivo, so it is possible to boost self-renewal.
Self-renewal is modulated by epigenetic modification. Gene transcription is altered by modifying histones and transcription factors by processes such as phosphorylation, acetylation, ubiquitylation, SUMOylation and methylation.
Self-renewal is linked to HOXgene expression.
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