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1、干 细 胞 总 论 (GENERAL IDEA ON STEM CELLS),一、干细胞的概念,“Stem cells” is a term to describe normal precursor cells that can give rise to multiple tissue types. Stem cell potentials: Self renewal Proliferation Differentiation,二、干细胞的特征 1.形态特征和生化特征 形态特征圆形或椭圆形，核质比大； 生化特征较高的端粒酶活性。 2.生长特征 增殖的缓慢性, G0 增殖的自稳性（区别与肿瘤细胞
2、的本 质特征，库量一定） 自我复制 多向分化和分化的不可逆性,三、干 细 胞 的 类 型 (续),by potential sources for stem cells: Embryonic stem cells derived from the inner cell mass of a blastocyst (a very early embryo). Adult stem cells stem cells found in adult tissues are referred to as adult stem cells. certain tissues of the body, from
3、 post- embryonic development through the normal life of any organism, require stem cells for normal turnover and repair. a good example is blood, but this is true for muscle and other connective tissue as well, and may be true for at least some nervous system cells.,Cell Cycle and Stem Cell Self Ren
4、ewal or Differentiation,Although it is still not clear what controls the decision to either self-renew or differentiate, or how the fate of a differentiating daughter cell is determined, the regulation of the cell cycle appears to play a key role in these processes. The eukaryotic cell cycle consist
5、s of alternating rounds of DNA replication (S phase) and cell division (M phase) separated by the gap phases G1 and G2 .,SCs exhibit slow cell cycle: G1 arrest, extending cell cycle progression,Progression through the cell cycle is controlled by the periodic activation of cyclin-dependent kinases (C
6、dks). Multiple Cdks have been identified in mammalian cells. In general, Cdks can be regulated by at least three independent mechanisms. First, Cdk kinase activity is dependent on its association with distinct cyclin proteins, and formation of these complexes is driven by cycles of cyclin synthesis
7、and degradation. Second, phosphorylation of Cdk kinase at a conserved threonine residue by Cdk activating kinase (CAK) is required for activity, whereas inhibitory phosphorylation within the ATP-binding site is regulated by the combined action of the Wee1 kinase and Cdc25 phosphatase. Finally, Cdk a
8、ctivity can be regulated by binding to a specific class of Cdk inhibitors (CKIs).,Progression through the cell cycle depends on cyclin-dependent kinase (Cdk)-mediated phosphorylation events,In early G1, D-type cyclins are synthesized and partner with Cdk4 And Cdk6. Late G1 is characterized by E-type
9、 cyclin expression and Cdk2 activity. The activation of these kinases results in the phosphorylation of crucial regulators of cell-cycle progression, such as pRb, which liberates activating E2Fs to drive S-phase entry. The crucial role for CDK activation in the decision to commit to cell division in
10、dicates the importance of finely tuned mechanisms by which to modulate these kinases. Indeed, in addition to the regulated synthesis and destruction of cyclins, Cdk activity can be adjusted by other mechanisms, including phosphorylation and direct regulation by a class of proteins known as cyclin de
11、pendent kinase inhibitors (CKIs).,Figure 2. The decision to commit to DNA replication is made at the G1-to-S transition by phosphorylation of the Rb pocket protein (green), resulting in the liberation of E2Fs (green) to activate gene expression required for S-phase entry. Rb phosphorylation, in turn
12、, depends on the coordinate regulation of cyclins (blue), cyclin-dependent kinases (blue), and Cdk inhibitors (yellow).,1. DNA DAMAGE-DEPENDENT CHECKPOINT In most eukaryotic cells, DNA damage delays cell cycle progression by inhibiting Cdk kinase activation at either the G2-to-M or G1-to-S-phase tra
13、nsition. In multicellular organisms, DNA damage activates a checkpoint control pathway that leads to either cell cycle arrest in G1 or G2, or programmed cell death, i.e., apoptosis. A key regulator is P53. P53 is a sequence-specific DNA-binding protein that activates the transcription of a variety o
14、f downstream effector genes. P53 is required for cell cycle arrest in G1, or apoptosis from G1 or G2 Mammalian cells also arrest the cell cycle in G2 in response to DNA damage. P53 can then trans-activate a number of genes, including IPT1/WAF1/p21, a potent inhibitor of CDK activities required for t
15、he G1 to S phase transition. The proposed role for p21 in cell cycle arrest is twofold; in addition to blocking CDK activity, p21 is also known to bind proliferating cell nuclear antigen (PCNA), a protein required for both DNA replication and DNA repair. Other potential candidates that might partici
16、pate in P53-dependent G1 arrest include the Gadd45, WIP1 Cyclin D1, and ABL genes.,Cell Cycle Checkpoints,DNA DAMAGE-DEPENDENT CHECKPOINT (continue) It is still a mystery as to why, in multicellular organisms, some cells arrest the cell cycle in response to DNA damage whereas others undergo apoptosis. Although the basis for this difference is poorly understood, P53 has been shown to be essential for both G1 arrest following DNA damage and apoptosis from G1 or G2. Apo
