Defects in NKG2D ligand expression result in failed tolerance induction at the maternal-fetal interface: A possible cause for recurrent miscarriage

Mesenchymal stem cells (MSCs) therapy has emerged as a potent therapeutic strategy to improve myocardial infarction. However MSCs therapy encounters a few obstacles regarding the poor viability of the transplanted cells. Therefore, it is important to explore a strategy to enhance post-transplanted MSC viability. To overcome this problem, several protocols were suggested mainly by activating PI3K/Akt pathway. The PI3K/Akt cascade regulates several cellular processes such as proliferation and apoptosis. Finasteride is a specific inhibitor of type II 5α-reductase; the enzyme converts testosterone (T) to the more potent androgen receptor agonist dihydrotestosterone (DHT). Testosterone is found to stimulate rapid phosphorylation of Akt, and thereby activate the PI3K/Akt pathway. This pathway could lead to decreased apoptosis of the MSCs via increasing the expression of Bcl-2 and reducing Bax expression. It has been also reported that DHT would confine the differentiation capacity of MSCs so that a reduction in DHT levels caused by Finasteride would be accompanied by increased facilitation in differentiation of MSCs to cardiomyocyte by means of the signals originating from the injured cardiac tissue. These mechanisms could propose the potential role for Finasteride to improve the MSCs therapy for myocardial infarction.     

Autophagy activation: a novel mechanism of atorvastatin to protect mesenchymal stem cells from hypoxia and serum deprivation via AMP-activated protein kinase/mammalian target of rapamycin pathway

Autophagy is a complex "self-eating" process and could be utilized for cell survival under stresses. Statins, which could reduce apoptosis in mesenchymal stem cells (MSCs) during both ischemia and hypoxia/serum deprivation (H/SD), have been proved to induce autophagy in some cell lines. We have previously shown that atorvastatin (ATV) could regulate AMP-activated protein kinase (AMPK), a positive modulator of autophagy, in MSCs. Thus, we hypothesized that autophagy activation through AMPK and its downstream molecule mammalian target of rapamycin (mTOR) may be a novel mechanism of ATV to protect MSCs from apoptosis during H/SD. Here, we demonstrated that H/SD induced autophagy in MSCs significantly as identified by increasing acidic vesicular organelle-positive cells, type II of light chain 3 (LC3-II) expression, and autophagosome formation. The levels of H/SD-induced apoptosis were increased by autophagy inhibitor 3-methyladenine (3-MA) while decreased by rapamycin, an autophagic inducer. ATV further enhanced the autophagic activity observed in MSCs exposed to H/SD. Treatment with 3-MA attenuated ATV-induced autophagy and abrogated the protective effects of ATV on MSC apoptosis, while rapamycin failed to cause additional effects on either autophagy or apoptosis compared with ATV alone. The phosphorylation of AMPK was upregulated whereas the phosphorylation of mTOR was downregulated in ATV-treated MSCs, which were both attenuated by AMPK inhibitor compound C. Further, treatment with compound C reduced the ATV-induced autophagy in MSCs under H/SD. These data suggest that autophagy plays a protective role in H/SD-induced apoptosis of MSCs, and ATV could effectively activate autophagy via AMPK/mTOR pathway to enhance MSC survival during H/SD.     

Insulin rescues ES cell-derived neural progenitor cells from apoptosis by differential regulation of Akt and ERK pathways

Transplantation of embryonic stem (ES) cell-derived neural progenitor cells (ES-NPCs) is one promising technology for the treatment of spinal cord injury. Promoting ES-NPC survival at the lesion site is critical for the successful treatment. We tested the role of insulin in promoting mouse ES-NPC survival. Cultured ES-NPCs survived when maintained in normoxia but underwent apoptosis when exposed to hypoxia. Insulin rescued ES-NPCs from hypoxia-induced cell death. This effect could be blocked by the phosphatidylinositol 3-kinase (PI3K)/Akt pathway inhibitor LY294002. In contrast, mitogen-activated protein kinase (MAP)/extracellular-signal-regulated kinase (ERK) pathway inhibitor U0126 potentiated insulin-mediated survival. Immunoblots revealed that insulin upregulated activation of Akt and inhibited ERK activation through the PI3K pathway. In addition, we showed that insulin reduced the activation of caspase-3, the key executor of apoptosis. In summary, our data suggest that insulin prevent apoptosis in ES-NPCs by activating Akt and inhibiting ERK through the PI3K pathway.     

Mesenchymal stem cells inhibition of chronic ethanol-induced oxidative damage via upregulation of phosphatidylinositol-3-kinase/Akt and modulation of extracellular signal-regulated kinase 1/2 activation in PC12 cells and neurons

It is well known that chronic ethanol consumption damages CNS through oxidative stress which results in many dysfunctions. Recently, it has been demonstrated that as a promising strategy to treat several neurological diseases, transplanted bone marrow-derived mesenchymal stem cells (MSCs) can secrete lots of protective factors that in turn promote function recovery. In the present study, we assessed the potential effects of MSCs conditioned medium (MSC-CM) against chronic ethanol-associated damage on PC12 cells and primary cortical neurons. We found that pretreatment with MSC-CM notably improved cell survival, prevented chronic ethanol-associated apoptosis and abolished the robust deterioration in oxidative status. In addition, we also discovered that chronic ethanol exposure induced an inactivation of phosphatidylinositol-3-kinase (PI3K)/Akt and a lasting activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in both PC12 cells and primary cortical neurons which were able to be reversed by MSC-CM. The PI3K inhibitor (LY294002) was able to reduce the antioxidative and cytoprotective effects conferred by MSC-CM, in part, and the ERK1/2 inhibitor (PD98059) was able to elicit significant protection from chronic ethanol cytotoxicity but not rescue the deterioration in oxidative status induced by chronic ethanol. Taken together, these findings provide the first evidence that MSCs might have potent antioxidant action to shield the apoptotic impairment from chronic ethanol exposure in PC12 cells and neurons, which is involved in upregulation of PI3K/Akt and modulation of ERK1/2 activation, at least partially.     

重组人促红细胞生成素与骨髓间充质干细胞的迁移及黏附

背景：促红细胞生成素可促进内皮祖细胞的增殖分化并增强其黏附性。 目的：观察重组人促红细胞生成素干预对人骨髓间充质干细胞迁移和黏附能力及相关细胞信号传导通路的影响。 方法：体外培养人骨髓间充质干细胞,使用重组人促红细胞生成素干预第6代人骨髓间充质干细胞。分别用PI3K/Akt通路特异抑制剂Ly294002或p38MAPK通路特异激动剂anisomycin或ERK1/2通路特异抑制剂U0126预处理。 结果与结论：重组人促红细胞生成素可使人骨髓间充质干细胞的PI3K/Akt通路磷酸化水平升高,抑制p38MAPK通路磷酸化水平,对人骨髓间充质干细胞的ERK通路和总Akt、总p38MAPK水平无明显影响。重组人促红细胞生成素作用组中迁移细胞数目显著高于对照组(P < 0.01),黏附细胞数亦明显增加(P < 0.01),PI3K/AKT通路特异抑制剂Ly294002预处理后重组人促红细胞生成素对迁移能力的作用消失,p38MAPK通路特异激动剂anisomycin预处理对两种作用影响均不明显。提示重组人促红细胞生成素具有增强人骨髓间充质干细胞迁移和黏附能力的作用,其增强迁移能力的作用与激活人骨髓间充质干细胞的PI3K/Akt通路有关,但是它对黏附能力的作用与PI3K/Akt和p38MAPK通路均无关。     

TGF-beta1 modulates Fas (APO-1/CD95)-mediated apoptosis of human pre-B cell lines

We have previously shown that Fas-induced apoptosis is markedly enhanced by IL-7 in human pre-B but not pro-B cell lines. In addition, pre-B cell receptor (pre-BCR) ligation significantly potentiates the IL-7 effects on Fas-triggered pre-B cell death. We show herein that transforming growth factor (TGF)-beta 1 sharply reduces Fas-induced death rate of pre-B but not pro-B cells. TGF-beta 1 causes inhibition of Fas-mediated disruption of mitochondrial transmembrane potential and cleavage of caspase 8, Bid and caspase 3. Bcl2 expression is markedly increased in TGF-beta 1-treated pre-B cells, whereas cellular FLICE-like inhibitory protein long (c-FLIPL), Bcl-XL, Bax, and Bad expression remains unchanged. TGF-beta 1 causes a selective growth arrest of pre-B cells in G0/G1 phase of the cell cycle and induces a partial down-modulation of both Fas and pre-BCR expression. All TGF-beta 1-mediated effects, but Bcl2 up-regulation, can be reproduced by the LY294002 phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor but not by inhibitors of the MAPK/ERK (MEK) and Janus kinase (Jak)/STAT pathways, which promote cell death. Akt phosphorylation is strongly inhibited by TGF-beta1 in pre-B but not pro-B cells and is not modified by Fas engagement. Altogether, our findings suggest that TGF-beta1 prevents Fas-induced apoptosis of pre-B lines by inhibiting PI3K pathway and by enhancing expression of Bcl2. They also suggest that the PI3K/Akt pathway is involved in the control of Fas and pre-BCR expression, a checkpoint in B cell development.     

Apelin 13: A novel approach to enhance efficacy of hypoxic preconditioned mesenchymal stem cells for cell therapy of diabetes

Recent studies have proposed cell therapy as an alternative therapeutic strategy for many disease states such as diabetes mellitus. Among different cell types mesenchymal stem cells (MSC) have attracted a significant attention based on their intriguing potentials. However MSC therapy is limited as a large portion of transplanted cells undergo apoptosis after transplantation. Therefore, proposing a strategy to overcome this obstacle may be of great value. Recent studies have shown that hypoxia preconditioning (HPC) may improve cell viability after transplantation. Both HPC and hyperglycemia are reported to exert effects by different levels of ROS overproduction. Overdose of ROS in this case would trigger the apoptosis and thereby decreased cell viability after transplantation. Apelin; the endogenous ligand for the previously orphaned G protein–coupled receptor APJ is shown to exert anti apoptotic effects On oxidative stress-induced apoptosis in MSCs via MAPK/ERK1/2 and PI3K/AKT signaling pathways. Accordingly it has been hypothesized that pretreatment of HPC-MSC_s with apelin 13 would be an effective approach to modify and possibly enhance the efficacy of MSCs in cell therapy of diabetes.     

Apelin 13: A novel approach to enhance efficacy of hypoxic preconditioned mesenchymal stem cells for cell therapy of diabetes

Recent studies have proposed cell therapy as an alternative therapeutic strategy for many disease states such as diabetes mellitus. Among different cell types mesenchymal stem cells (MSC) have attracted a significant attention based on their intriguing potentials. However MSC therapy is limited as a large portion of transplanted cells undergo apoptosis after transplantation. Therefore, proposing a strategy to overcome this obstacle may be of great value. Recent studies have shown that hypoxia preconditioning (HPC) may improve cell viability after transplantation. Both HPC and hyperglycemia are reported to exert effects by different levels of ROS overproduction. Overdose of ROS in this case would trigger the apoptosis and thereby decreased cell viability after transplantation. Apelin; the endogenous ligand for the previously orphaned G protein–coupled receptor APJ is shown to exert anti apoptotic effects On oxidative stress-induced apoptosis in MSCs via MAPK/ERK1/2 and PI3K/AKT signaling pathways. Accordingly it has been hypothesized that pretreatment of HPC-MSC_s with apelin 13 would be an effective approach to modify and possibly enhance the efficacy of MSCs in cell therapy of diabetes.     

Akt、ERK1/2活化在脑源性神经营养因子促血管新生中的作用

目的： 探讨脑源性神经营养因子(BDNF) 促进血管新生的作用及其参与的信号通路,为抗肿瘤血管生成的研究提供新的实验依据。 方法: 以人脐静脉内皮细胞为对象,采用Western 印迹方法检测细胞内磷酸化Akt、ERK1/2蛋白质的表达； 采用Transwell小室迁移实验、管腔形成实验评价体外内皮细胞血管新生的能力，MTT法检测内皮细胞增殖 活性，FITC-Annexin-Ⅴ/PI双染流式细胞术分析细胞凋亡。 结果: BDNF以时间依赖性方式激活PI3K/Akt 和MEK1/ERK信号通路。分别应用PI3K激酶抑制剂Ly294002、 MEK1激酶抑制剂PD98059可以明显阻断BDNF对PI3K/Akt、MEK1/ERK信号通路的激活。100 μg/L 的BDNF体 外促内皮细胞血管新生能力与 25 μg/L 血管内皮生长因子（VEGF）相当， 其中BDNF诱导的细胞迁移分 别被Ly294002和PD98059阻断，其抑制率分别约为74%和36%；同样，Ly294002、PD98059可部分阻断BDNF诱 导的小管形成效应，其阻断率分别约57%和37%；而BDNF的促增殖效应仅被PD98059拮抗，抑制凋亡效应仅受Ly294002影响。 结论: BDNF在体外有促血管新生的作用。PI3K/Akt 和MEK1/ERK信号通路以不同机制共同调节这一过程,其中PI3K/Akt信号通路起着更为重要的调节作用。     

Enhancement of MSC adhesion and therapeutic efficiency in ischemic heart using lentivirus delivery with periostin

Many approaches have shown beneficial effects of modified mesenchymal stem cells (MSCs) for treatment of infarcted myocardium, but have primarily focused on enhancing the survival of transplanted MSCs. Here, we show the dual benefits of periostin-overexpressing MSCs (p-MSCs) for infarcted myocardium. P-MSCs led to the marked histological and functional recovery of infarcted myocardium by enhancing survival of MSCs and directly preventing apoptosis of cardiomyocytes. Survival of p-MSCs themselves and cardiomyocytes co-cultured with p-MSCs or treated with the conditioned media from p-MSCs was significantly increased under hypoxic conditions. Decreases in adhesion-related integrins were reversed in cardiomyocytes co-cultured with p-MSCs, followed by increases in p-PI3K and Akt, indicating that periostin activates the PI3K pathway through adhesion-related integrins. When p-MSCs were injected into myocardial infarcted rats, histological pathology and cardiac function were significantly improved compared to MSC-injected controls. Thus, periostin might be a new target of therapeutic treatments using MSCs as carriers for infarcted myocardium.     

Induction of macrophage migration inhibitory factor by lysophosphatidic acid: relevance to tumor growth and angiogenesis

Macrophage migration inhibitory factor (MIF) plays an important role not only in the immune system, but also in tumorigenesis. Lysophosphatidic acid (LPA), a unique lipid mediator, shares several biological functions with MIF, including promotion of tumor cell growth and associated angiogenesis. In this study, we investigated the signaling cross-talk between these two molecules during tumorigenesis and angiogenesis. We first examined the expression of MIF mRNA on a murine colon cancer cell line, colon 26, by LPA. We found that LPA enhanced the expression of MIF mRNA in a dose-dependent manner in vitro. In parallel, LPA stimulated cell growth and up-regulated the vascular endothelial growth factor (VEGF). These effects were dramatically blocked by 21 base double strand (ds) RNA specific for mouse MIF mRNA (RNAi). In vivo, colon 26 cells treated with MIF dsRNA were injected into the backs of mice. The size of tumor volumes became significantly smaller than that of controls. Angiogenesis examined by a Millipore chamber method was also suppressed by the MIF dsRNA. Next, we evaluated the signal transduction pathway relevant to the mitogen-activated protein kinase (MAPK) and Akt/PI3K pathways in response to LPA by RNAi. Ras activation and phosphorylation of Akt and ERK1/2 were strongly suppressed by the dsRNA. On the other hand, tyrosine phosphorylation was minimally changed by the treatment. Taken together, these results suggest that MIF could promote both tumor cell growth and angiogenesis induced by LPA via both the Ras-MAPK and Ras-Akt/PI3K signaling pathways.     

Bisdemethoxycurcumin protects endothelial cells against t-BHP-induced cell damage by regulating the phosphorylation level of ERK1/2 and Akt

Curcuminoids are the major active components extracted from Curcuma longa and are well known for their antioxidant effects. Previous studies have reported that the antioxidant properties of curcuminoids are mainly attributed to their free radical scavenging abilities. However, whether there are other mechanisms besides the non-enzymatic process and how they are involved, still remains unknown. In the present study, we explored the protective effects of bisdemethoxycurcumin (Cur3) against tert-butyl hydroperoxide (t-BHP)-induced cytotoxicity in human umbilical vein endothelial cells (HUVECs), focusing on the effect of Cur3 on the regulation of the phosphatidylinositol 3-kinase (PI3K)/Akt and the mitogen-activated protein kinase (MAPK) pathways. The pre-treatment with Cur3 inhibited t-BHP-induced cell damage dose-dependently, which was evident by the increased cell viability and the corresponding decrease in lactate dehydrogenase release. The pre-treatment with Cur3 also attenuated t-BHP-induced cell morphological changes and apoptosis. MAPKs, including p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinase 1/2 (ERK1/2), as well as PI3K/Akt have been reported to be involved in proliferation, apoptosis and differentiation under various stress stimulations. The pre-treatment with Cur3 decreased t-BHP-induced ERK1/2 phosphorylation and increased t-BHP-induced Akt phosporylation but did not affect the phosphorylation of p38 or JNK. In addition, the Cur3-induced increase in cell viability was attenuated by the treatment with wortmannin or LY294002, the upstream inhibitors of Akt, and was enhanced by the treatment with 2-[2'-amino-3'-methoxyphenyl]-oxanaphthalen-4-one (PD98059), an upstream inhibitor of ERK1/2. These results suggest that the ERK1/2 and PI3K/Akt signaling pathways could be involved in the protective effects of Cur3 against t-BHP-induced damage in HUVECs.     

Roles of the PI3K/Akt pathway in Epstein-Barr virus-induced cancers and therapeutic implications

Viruses have been shown to be responsible for 10%-15% of cancer cases. Epstein-Barr virus (EBV) is the first virus to be associated with human malignancies. EBV can cause many cancers, including Burkett’s lymphoma, Hodgkin’s lymphoma, post-transplant lymphoproliferative disorders, nasopharyngeal carcinoma and gastric cancer. Evidence shows that phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) plays a key role in EBV-induced malignancies. The main EBV oncoproteins latent membrane proteins (LMP) 1 and LMP2A can activate the PI3K/Akt pathway, which, in turn, affects cell survival, apoptosis, proliferation and genomic instability via its downstream target proteins to cause cancer. It has also been demonstrated that the activation of the PI3K/Akt pathway can result in drug resistance to chemotherapy. Thus, the inhibition of this pathway can increase the therapeutic efficacy of EBV-associated cancers. For example, PI3K inhibitor Ly294002 has been shown to increase the effect of 5-fluorouracil in an EBV-associated gastric cancer cell line. At present, dual inhibitors of PI3K and its downstream target mammalian target of rapamycin have been used in clinical trials and may be included in treatment regimens for EBV-associated cancers.     

IL-12 inhibits glucocorticoid-induced T cell apoptosis by inducing GMEB1 and activating PI3K/Akt pathway

Interleukin (IL)-12 is an important pro-inflammatory cytokine that has been shown to play a role in T cell survival, at least in part by activating the PI3K/Akt pathway. Glucocorticoid modulatory element binding protein (GMEB)1 and 2 are closely related proteins that modify the glucocorticoid receptor binding locus and thus modulate glucocorticoid-mediated gene induction effects, including apoptosis. GMEB1 associates with caspases and prevents apoptosis of cells in the nervous system. We have observed, in preliminary studies, that IL-12 up-regulates GMEB mRNA in human T cells, and postulated that this may contribute to the anti-apoptotic effect of IL-12 on T cells, in particular with regard to glucocorticoid induced apoptosis. Here, we confirm that IL-12 rescue of dexamethasone induced T cell apoptosis involves the PI3K/Akt pathway and that IL-12 induces GMEB1 and GMEB2. A siRNA knockdown of GMEB1 reverses the protective effect of IL-12 on dexamethasone induced T cell apoptosis. Thus, IL-12 protects T cells from glucocorticoid induced apoptosis via PI3K/Akt pathway and via induction of GMEB1, which is likely to reduce transactivation of the glucocorticoid receptor and induction of apoptotic genes. As glucocorticoid induced apoptosis occurs both in physiological and pathological/therapeutic situations, and IL-12 is actively involved in a variety of inflammatory and immune responses, the ability of IL-12 to inhibit steroid responses and increase T cell survival through GMEB1 has wide ranging implications. Manipulating GMEB may be used therapeutically to enhance the resistance or the sensitivity to steroids.     

人甲壳质酶蛋白40通过PI3K/Akt信号通路调控膝骨性关节炎兔软骨细胞的凋亡

文题释义：膝骨关节炎(knee osteoarthritis，KOA)：常发生在中老年人群，其病理过程涉及软骨基质退行性病变、软骨细胞性状显著性改变和数量明显减少。在外力及内部环境改变等因素影响下，软骨细胞外基质、软骨细胞及软骨下骨的合成和降解动态平衡出现紊乱，软骨细胞大量凋亡使得软骨修复、重塑等稳定状态出现异常，上述情况均可诱导膝骨关节炎的发生。人甲壳质酶蛋白40(YKL-40)：是一种广泛存在于关节滑膜细胞、软骨细胞中的软骨糖蛋白，具有多种生物学功能作用：①促进软骨细胞、成骨细胞的增殖生长及分化；②促进新生血管组织的形成；③调控细胞外基质的重构过程；④协助细胞适应生长环境的显著性改变及缺氧等病理损伤，此外在软骨细胞凋亡方面也发挥一定作用。背景：由于PI3K/Akt信号通路与骨组织生理代谢之间存在着密切的联系，而人甲壳质酶蛋白40(YKL-40)对乳腺癌发病机制中的PI3K/Akt信号通路具有一定调控作用，由此推测YKL-40可能通过PI3K/Akt信号通路对膝骨性关节炎软骨细胞凋亡进行调控。 目的：研究YKL-40通过PI3K/Akt信号通路调控膝骨性关节炎兔软骨细胞凋亡的作用机制。方法：①将新西兰大白兔随机分为2组，膝骨性关节炎模型组采用前交叉韧带离断术制作右后膝骨性关节炎动物模型，正常对照组仅切开右后膝关节囊，造模后第6周取材并分离软骨细胞，予以软骨组织苏木精-伊红染色及Mankin组织学评分，同时免疫组化染色检测软骨细胞Ⅱ型胶原表达；②正常对照组兔第2代软骨细胞为正常对照组；将膝骨性关节炎模型组兔第2代软骨细胞分为4组，模型组仅予以含体积分数10%胎牛血清的高糖DMEM培养基培养，模型+YKL组培养基中加入100 μg/L YKL-40干预，模型+LY组培养基中加入50 µmol/L PI3K通路抑制剂LY294002干预，模型+YKL+LY组：培养基中加入100 μg/L YKL-40和50 µmol/L LY294002干预，采用免疫印迹法检测各组软骨细胞Ⅱ型胶原、基质金属蛋白酶13、Akt、p-Akt、P53、Bcl-2蛋白表达水平。结果与结论：①经软骨组织苏木精-伊红染色、Mankin组织学评分及软骨细胞Ⅱ型胶原免疫组化染色证实，膝骨性关节炎动物模型构建和软骨细胞培养均获得成功；②模型组Ⅱ型胶原、Bcl-2、p-Akt蛋白表达明显低于正常对照组(P < 0.05)，基质金属蛋白酶13、P53蛋白表达明显高于正常对照组(P < 0.05)；与模型组比较，模型+YKL组上述指标得到明显改善(P < 0.05)，而模型+LY组上述指标则进一步恶化(P < 0.05)，模型+YKL+LY组上述指标与模型组比较无显著性差异(P > 0.05)，但与模型+YKL组和模型+LY组比较有显著性差异(P < 0.05)；各组Akt蛋白表达水平比较无显著性差异(P > 0.05)。提示：YKL-40可通过激活活化PI3K/Akt信号通路，起到抑制兔膝骨性关节炎软骨细胞凋亡，加快软骨损伤修复和延缓软骨退行性改变的作用，可作为临床治疗膝骨性关节炎的新作用靶点。ORCID: 0000-0002-7889-445X(田胜兰) 中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程     

整合素传递力学信号影响间充质干细胞分化的研究进展

简述硬度的可控性及其控制方法、不同硬度调控间充质干细胞(mesenchymal stem cells,MSCs)分化的相应方向和整合素在硬度调控MSCs分化的信号通路中的作用。其中,重点说明整合素在硬度调控MSCs分化的信号通路中的作用。硬度调控MSCs分化的信号通路包括:Rho/ROCK信号通路、整合素/FAK信号通路、ERK信号通路、JNK信号通路、Wnt-β-catenin信号通路和PI3K/Akt信号通路等。而整合素作为跨膜异二聚体糖蛋白,参与部分信号通路传递力学信号给MSCs。不同的整合素家族参与不同的信号通路来调控MSCs向不同方向分化,且这些信号通路间存在相互影响。研究结论为组织修复、器官再造和再生医学等方面的应用提供理论依据。     

PI3K/Akt信号通路及其抑制剂的研究进展

磷脂酰肌醇3激酶（PI3K）/丝氨酸-苏氨酸激酶（Akt）信号通路在信号转导的调控中扮演着重要角色,能调节细胞增殖、凋亡、代谢、运动、血管生成等生物过程。与其他信号通路相比,PI3K/Akt信号通路的组成部分更庞大,在肿瘤中更多见。目前已证实多种肿瘤中存在PI3K/Akt信号通路的超活化,对肿瘤细胞的存活、生长、运动、血管生成和代谢意义重大。因此,抑制PI3K和与通路相关的成分可能会使肿瘤生长受抑,使患者预后改善。PI3K/Akt信号通路抑制剂包括针对单一成分的抑制剂和双重抑制剂。目前大量的PI3K抑制剂已在临床前期研究中取得良好结果,有些已经在血液恶性肿瘤和实体肿瘤中进行了临床试验。在此综述中,我们简单的总结了PI3K-AKt通路的研究成果,讨论了PI3K抑制剂从临床前研究到临床研究的发展前景。