Reprogramming of and Programming by Mesenchymal Stem Cells (MSC)

间充质干细胞 (MSC) 的重编程和编程

• 批准号: 152332799
• 负责人: Professor Dr. Martin Zenke
• 金额: --
• 依托单位: Klinik für Onkologie, Hämatologie und Stammzelltransplantation (Med. Klinik IV)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/152332799?language=en
• 关键词: Reprogramming; Programming; Mesenchymal; Stem; Cells

Stem cells are characterized by two unique properties that put them aside from most somatic cells: their exceptionally high self-renewal activity and their multilineage differentiation potential. In the last few years we experienced further findings that add to these stem cell properties: First, reprogramming can reset the transcriptional state of a somatic genome to a pluripotent state and make somatic cells acquire stem cell properties. Second, stem cells communicate with somatic cells and can have adetermining impact on somatic cell function. Thus, these novel findings significantly broaden our knowledge on the molecular principles of stem cell biology and we will address these issues in this project proposal by employing mesenchymal stem cells (MSC).MSC represent a multipotent somatic stem cell population that is present in various adult tissues, including bone marrow. MSC can differentiate into various cell types, such as osteoblasts, chondrocytes and adipocytes, and also have a profound immunomodulatory function both in vivo and in vitro. In previous work the applicants found that bone marrow Flkl"*" MSC programme mature "inflammatory" antigen presenting dendritic cells (DC) into a distinct regulatory DC type that suppresses T cell activity via Jagged-notch signalling.In this project proposal we wish to continue our collaboration and to investigate (i) reprogramming of Flkl"*" MSC into induced pluripotent stem cells (iPS cells) and explore their potential application in skin disease and (ii) to further investigate the impact of Flk1+ MSC on programming of DC into regulatory DC. The collaborating laboratories have an established expertise in MSC, iPS cell and DC biology and are well prepared to address the following specific questions:(1) Which factors and/or conditions are required for reprogramming of Flk1 "•" MSC to pluripotency and for generating iPS cells?(2) How do Flk1+ MSC-derived iPS cells relate to IPS cells derived from mouse embryo fibroblasts (MEF) and neural stem cells (NSC) and are these iPS cells useful in a skin disease model of dystrophic epidermolysis bullosa.(3) What are the underiying molecular principles for the ability of Flk1+ MSC to programme mature "inflammatory" DC into inhibitory MSC-DC?(4) Do Flkl + MSC have an impact on further DC subsets, such as plasmacytoid DC (pDC) and if so what are the biological outcome and underlying mechanisms?This project proposal builds on previous work of the applicants, including collaborative work on MSC-DC, and the results are expected to have implications on patient-specific cell-based therapies.

干细胞具有两个独特的特性，使它们与大多数体细胞不同：它们异常高的自我更新活性和它们的多谱系分化潜力。在过去的几年里，我们经历了进一步的发现，增加了这些干细胞的特性：首先，重编程可以重置体细胞基因组的转录状态到多能状态，使体细胞获得干细胞特性。第二，干细胞与体细胞交流，并对体细胞功能产生决定性影响。因此，这些新的发现大大拓宽了我们对干细胞生物学的分子原理的知识，我们将通过采用间充质干细胞（MSC）在本项目提案中解决这些问题。MSC代表存在于各种成人组织（包括骨髓）中的多能体干细胞群体。MSC可以分化为成骨细胞、软骨细胞和脂肪细胞等多种细胞类型，并在体内外均具有显著的免疫调节功能。在先前的工作中，申请人发现骨髓Flkl”*”MSC将成熟的“炎性”抗原呈递树突状细胞（DC）编程为独特的调节性DC类型，其通过锯齿状缺口信号传导抑制T细胞活性。在本项目提案中，我们希望继续我们的合作并研究（i）Flkl”*”MSC重编程为诱导多能干细胞（ii）进一步研究Flk 1 + MSC对DC编程为调节性DC的影响。合作实验室在MSC、iPS细胞和DC生物学方面具有成熟的专业知识，并为解决以下具体问题做好了充分的准备：（1）Flk 1 + MSC重编程为多能性和产生iPS细胞需要哪些因素和/或条件？(2)Flk 1 + MSC衍生的iPS细胞与来自小鼠胚胎成纤维细胞（MEF）和神经干细胞（NSC）的IPS细胞如何相关，以及这些iPS细胞在营养不良性大疱性表皮病的皮肤病模型中是否有用。(3)Flk 1 + MSC将成熟的“炎性”DC编程为抑制性MSC-DC的能力的分子基础是什么？(4)Flkl + MSC对其他DC亚群如浆细胞样DC（pDC）有影响吗？如果有，生物学结果和潜在机制是什么？该项目提案建立在申请人之前的工作基础上，包括MSC-DC的合作工作，预计结果将对患者特异性细胞治疗产生影响。