5.4 KiB
| title | chunk | source | category | tags | date_saved | instance |
|---|---|---|---|---|---|---|
| Biochemical cascade | 5/9 | https://en.wikipedia.org/wiki/Biochemical_cascade | reference | science, encyclopedia | 2026-05-05T10:46:07.942614+00:00 | kb-cron |
=== Stem cells === Self-renewal and differentiation abilities are exceptional properties of stem cells. These cells can be classified by their differentiation capacity, which progressively decrease with development, in totipotents, pluripotents, multipotents and unipotents. Self-renewal process is highly regulated from cell cycle and genetic transcription control. There are some signaling pathways, such as LIF/JAK/STAT3 (Leukemia inhibitory factor/Janus kinase/Signal transducer and activator of transcription 3) and BMP/SMADs/Id (Bone morphogenetic proteins/ Mothers against decapentaplegic/ Inhibitor of differentiation), mediated by transcription factors, epigenetic regulators and others components, and they are responsible for self-renewal genes expression and inhibition of differentiation genes expression, respectively. At cell cycle level there is an increase of complexity of the mechanisms in somatic stem cells. However, it is observed a decrease of self-renewal potential with age. These mechanisms are regulated by p16Ink4a-CDK4/6-Rb and p19Arf-p53-P21Cip1 signaling pathways. Embryonic stem cells have constitutive cyclin E-CDK2 activity, which hyperphosphorylates and inactivates Rb. This leads to a short G1 phase of the cell cycle with rapid G1-S transition and little dependence on mitogenic signals or D cyclins for S phase entry. In fetal stem cells, mitogens promote a relatively rapid G1-S transition through cooperative action of cyclin D-CDK4/6 and cyclin E-CDK2 to inactivate Rb family proteins. p16Ink4a and p19Arf expression are inhibited by Hmga2-dependent chromatin regulation. Many young adult stem cells are quiescent most of the time. In the absence of mitogenic signals, cyclin-CDKs and the G1-S transition are suppressed by cell cycle inhibitors including Ink4 and Cip/Kip family proteins. As a result, Rb is hypophosphorylated and inhibits E2F, promoting quiescence in G0-phase of the cell cycle. Mitogen stimulation mobilizes these cells into cycle by activating cyclin D expression. In old adult stem cells, let-7 microRNA expression increases, reducing Hmga2 levels and increasing p16Ink4a and p19Arf levels. This reduces the sensitivity of stem cells to mitogenic signals by inhibiting cyclin-CDK complexes. As a result, either stem cells cannot enter the cell cycle, or cell division slows in many tissues. Extrinsic regulation is made by signals from the niche, where stem cells are found, which is able to promote quiescent state and cell cycle activation in somatic stem cells. Asymmetric division is characteristic of somatic stem cells, maintaining the reservoir of stem cells in the tissue and production of specialized cells of the same. Stem cells show an elevated therapeutic potential, mainly in hemato-oncologic pathologies, such as leukemia and lymphomas. Little groups of stem cells were found into tumours, calling cancer stem cells. There are evidences that these cells promote tumor growth and metastasis.
=== Oocytes === The oocyte is the female cell involved in reproduction. There is a close relationship between the oocyte and the surrounding follicular cells which is crucial to the development of both. GDF9 and BMP15 produced by the oocyte bind to BMPR2 receptors on follicular cells activating SMADs 2/3, ensuring follicular development. Concomitantly, oocyte growth is initiated by binding of KITL to its receptor KIT in the oocyte, leading to the activation of PI3K/Akt pathway, allowing oocyte survival and development. During embryogenesis, oocytes initiate meiosis and stop in prophase I. This arrest is maintained by elevated levels of cAMP within the oocyte. It was recently suggested that cGMP cooperates with cAMP to maintain the cell cycle arrest. During meiotic maturation, the LH peak that precedes ovulation activates MAPK pathway leading to gap junction disruption and breakdown of communication between the oocyte and the follicular cells. PDE3A is activated and degrades cAMP, leading to cell cycle progression and oocyte maturation. The LH surge also leads to the production of progesterone and prostaglandins that induce the expression of ADAMTS1 and other proteases, as well as their inhibitors. This will lead to degradation of the follicular wall, but limiting the damage and ensuring that the rupture occurs in the appropriate location, releasing the oocyte into the fallopian tubes. Oocyte activation depends on fertilization by sperm. It is initiated with sperm's attraction induced by prostaglandins produced by the oocyte, which will create a gradient that will influence the sperm's direction and velocity. After fusion with the oocyte, PLC ζ of the spermatozoa is released into the oocyte leading to an increase in Ca2+ levels that will activate CaMKII which will degrade MPF, leading to the resumption of meiosis. The increased Ca2+ levels will induce the exocytosis of cortical granules that degrade ZP receptors, used by sperm to penetrate the oocyte, blocking polyspermy. Deregulation of these pathways will lead to several diseases like, oocyte maturation failure syndrome which results in infertility. Increasing our molecular knowledge of oocyte development mechanisms could improve the outcome of assisted reproduction procedures, facilitating conception.