Sze Siu Kwan, de Kleijn Dominique P V, Lai Ruenn Chai, Khia Way Tan Eileen, Zhao Hui, Yeo Keng Suan, Low Teck Yew, Lian Qizhou, Lee Chuen Neng, Mitchell Wayne, El Oakley Reida Menshawe, Lim Sai-Kiang
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
Mol Cell Proteomics. 2007 Oct;6(10):1680-9. doi: 10.1074/mcp.M600393-MCP200. Epub 2007 Jun 11.
Transplantation of mesenchymal stem cells (MSCs) has been used to treat a wide range of diseases, and the mechanism of action is postulated to be mediated by either differentiation into functional reparative cells that replace injured tissues or secretion of paracrine factors that promote tissue repair. To complement earlier studies that identified some of the paracrine factors, we profiled the paracrine proteome to better assess the relevance of MSC paracrine factors to the wide spectrum of MSC-mediated therapeutic effects. To evaluate the therapeutic potential of the MSC paracrine proteome, a chemically defined serum-free culture medium was conditioned by MSCs derived from human embryonic stem cells using a clinically compliant protocol. The conditioned medium was analyzed by multidimensional protein identification technology and cytokine antibody array analysis and revealed the presence of 201 unique gene products. 86-88% of these gene products had detectable transcript levels by microarray or quantitative RT-PCR assays. Computational analysis predicted that these gene products will significantly drive three major groups of biological processes: metabolism, defense response, and tissue differentiation including vascularization, hematopoiesis, and skeletal development. It also predicted that the 201 gene products activate important signaling pathways in cardiovascular biology, bone development, and hematopoiesis such as Jak-STAT, MAPK, Toll-like receptor, transforming growth factor-beta, and mTOR (mammalian target of rapamycin) signaling pathways. This study identified a large number of MSC secretory products that have the potential to act as paracrine modulators of tissue repair and replacement in diseases of the cardiovascular, hematopoietic, and skeletal tissues. Moreover our results suggest that human embryonic stem cell-derived MSC-conditioned medium has the potency to treat a variety of diseases in humans without cell transplantation.
间充质干细胞（MSC）移植已被用于治疗多种疾病，其作用机制据推测是通过分化为替代受损组织的功能性修复细胞，或分泌促进组织修复的旁分泌因子来介导的。为补充早期鉴定出一些旁分泌因子的研究，我们对旁分泌蛋白质组进行了分析，以更好地评估MSC旁分泌因子与MSC介导的广泛治疗效果之间的相关性。为评估MSC旁分泌蛋白质组的治疗潜力，使用临床合规方案，用人胚胎干细胞来源的MSC对化学成分明确的无血清培养基进行条件培养。通过多维蛋白质鉴定技术和细胞因子抗体阵列分析对条件培养基进行分析，结果显示存在201种独特的基因产物。通过微阵列或定量RT-PCR分析，这些基因产物中有86 - 88%具有可检测的转录水平。计算分析预测，这些基因产物将显著驱动三大类生物学过程：代谢、防御反应以及包括血管生成、造血和骨骼发育在内的组织分化。该分析还预测，这201种基因产物可激活心血管生物学、骨骼发育和造血过程中的重要信号通路，如Jak-STAT、MAPK、Toll样受体、转化生长因子-β和mTOR（雷帕霉素哺乳动物靶标）信号通路。本研究鉴定出大量具有作为旁分泌调节剂潜力的MSC分泌产物，这些产物可在心血管、造血和骨骼组织疾病中调节组织修复和替代。此外，我们的结果表明，人胚胎干细胞来源的MSC条件培养基在不进行细胞移植的情况下具有治疗人类多种疾病的潜力。
