Reprogramming of and Programming by Mesenchymal Stem Cells (MSC)

• Applicant: Professor Dr. Martin Zenke
• Subject Area: Dermatology
• Term: from 2009 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 152332799

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.

• DFG Programme: Research Grants
• International Connection: China
• Participating Person: Professor Robert Chunhua Zhao, Ph.D.