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首页> 外文期刊>International journal of molecular medicine >Genome-wide analysis of murine bone marrow?derived very small embryonic-like stem cells reveals that mitogenic growth factor signaling pathways play a crucial role in the quiescence and ageing of these cells
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Genome-wide analysis of murine bone marrow?derived very small embryonic-like stem cells reveals that mitogenic growth factor signaling pathways play a crucial role in the quiescence and ageing of these cells

机译：对小鼠骨髓来源的非常小的胚胎样干细胞进行全基因组分析后发现，促有丝分裂生长因子信号通路在这些细胞的静止和衰老中起着至关重要的作用

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It has been postulated that the most primitive population of stem cells, Oct4+Sca-1+Lin-CD45- very small embryonic-like stem cells (VSELs), differentiate into tissue-committed stem cells in adult mice. However, Oct4+ VSELs remain quiescent in adult tissues and do not form teratomas. In thi study, we report the characteristics of the VSEL transcriptome by gene set enrichment analysis employing a microarray database established from 20?murine bone marrow-derived, FACS-sorted VSELs in comparison with hematopoietic stem cells and embryonic stem cells. In the Oct4+ VSELs, we observed the upregulation of tissue-specific gene sets and a gene set encoding the complement-coagulation cascade. By contrast, in the VSELs, we observed the downregulation of genes involved in the UV radiation response, mRNA processing and mitogenic growth factor signaling [e.g., insulin-like growth factor?1 (IGF-1) and neurotrophic tyrosine kinase receptor?A (TRKA), as well as the ERK and PI3K pathways]. Employing leading-edge subset analysis and real-time PCR assays, we observed that several genes, such as growth factor receptor-bound protein?2 (Grb2), son of sevenless homolog?1 (Sos1), SHC (Src homology 2 domain containing) transforming protein 1 (Shc1), mitogen-activated protein kinase kinase?1 (Map2k1), v-akt murine thymoma viral oncogene homolog?3 (Akt3), Elk1, ribosomal protein S6 kinase, 90kDa, polypeptide?3 (Rps6kA3), glycogen synthase kinase?3β (Gsk3β) and casein kinase?2, alpha?1 polypeptide (Csnk2A1), which are involved in mitogenic growth factor signaling pathways, were commonly downregulated in the VSELs. Notably, this repression was reversed in the VSELs co-cultured over a C2C12 supportive cell-line, whereby they are induced to form VSEL-derived spheres (VSEL-DSs); thus, they are enriched, forming more differentiated stem cells. Therefore, we suggest that the repression of mitogenic growth factor signaling (e.g.,?through the IGF-1 receptor) may prevent uncontrolled Oct4+ VSEL proliferation and teratoma formation. Thus, restoring the responsiveness to mitogenic growth factors may be a crucial step in employing these cells in regenerative medicine.
机译：据推测，成年小鼠中最原始的干细胞群体，即Oct4 + Sca-1 + Lin-CD45-非常小的胚胎样干细胞（VSEL）分化为组织定型干细胞。但是，Oct4 + VSEL在成人组织中保持静止，不会形成畸胎瘤。在这项研究中，我们通过基因组富集分析报告了VSEL转录组的特征，该基因组分析使用了由20？鼠骨髓来源的，FACS分选的VSEL与造血干细胞和胚胎干细胞相比建立的微阵列数据库。在Oct4 + VSEL中，我们观察到组织特异性基因集和编码补体-凝血级联反应的基因集的上调。相比之下，在VSEL中，我们观察到与紫外线辐射响应，mRNA加工和有丝分裂生长因子信号传导有关的基因的下调[例如，胰岛素样生长因子？1（IGF-1）和神经营养性酪氨酸激酶受体？A（ TRKA），以及ERK和PI3K途径]。利用前沿的子集分析和实时PCR分析，我们观察到几个基因，例如生长因子受体结合蛋白？2（Grb2），七无同源蛋白？1（Sos1）的儿子，SHC（Src同源2域）转化蛋白1（Shc1），促分裂原活化蛋白激酶激酶1（Map2k1），v-akt鼠胸腺瘤病毒致癌基因同源物3（Akt3），Elk1，核糖体蛋白S6激酶，90kDa，多肽3（Rps6kA3），糖原合酶激酶α3β（Gsk3β）和酪蛋白激酶α2，αβ1多肽（Csnk2A1）参与有丝分裂生长因子信号通路，通常在VSEL中被下调。值得注意的是，这种抑制作用在通过C2C12支持细胞系共培养的VSEL中被逆转，从而被诱导形成VSEL衍生球（VSEL-DS）。因此，它们被富集，形成更多分化的干细胞。因此，我们建议抑制有丝分裂生长因子信号转导（例如，通过IGF-1受体）可防止不受控制的Oct4 + VSEL增殖和畸胎瘤形成。因此，恢复对促有丝分裂生长因子的反应性可能是在再生医学中使用这些细胞的关键步骤。

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