Transcriptome-based approach to identify biomimetics for stem cell-derived factors regulating tissue regeneration

Project Details: Stem cells promote the regeneration of numerous tissues in the human body. However the mechanisms underpinning their restorative ability remain to be elucidated. An increasing body of evidence demonstrates that stem cells do not incorporate into newly formed tissue but rather instruct resident cells, via secreted molecules, to activate repair mechanisms. Thus a paradigm shift has been to accept that factors produced by stem cells rather than the stem cells are the efficacious entities controlling tissue repair. This concept represents an unprecedented opportunity to identify and develop compounds, on an industrial scale, that are not only defined but also individually analysed, thus expiditing their safe use to promote tissue regeneration without the involvement of cells.

Two major impediments have prevented a systematic approach to identifying biomimetics for secreted stem cells factors. The first was the absence of a robust platform that gives a biological response to stem cells-derived factors. The second was at the other end of the discovery platform; the lack of large number of biologically safe compounds that evoke a change in cell phenotype. Both these hurdles have been recently overcome, firstly through our discovery that human adipose-derived mesenchymal stem cells (ADMSC) secrete factors (SF) that promote cell proliferation, migration and protect against stress-induced senescence. The second development has been the profiling of over 1300 FDA-approved compounds in a variety of cells to develop large data sets that allows each drug to be profiled not on its biological effect but in terms of gene transcription (The Connectivity Map, C-Map). The key innovation is to use bioinformatic approaches to match the changes in transcription evoked by ADMSC-derived factors in their ability to regulate proliferation, migration and senescence to those promulgated by the library of safe compounds, leading to the identification of biomimetics for stem cell-derived factors regulating tissue regeneration.

Aims:
1. Develop transcriptional profile changes in cell division, cell migration and cell senescence assays through the activity of ADMSC-SF.
2. Perform bioinformatic analysis of transcriptome data and identify activated signalling pathways.
3. Compare the ADMSC SF cell assay transcriptome signatures with the database of FDA compounds [C-Map] to identify, score and rank correlating biomimetics.
4. Investigate biomimetic properties of the 10 strongest compounds in cell division, cell migration and cell senescence assays.
5. Compare ADMSC SF to 3 biomimetics in animal tissue regeneration models.
6. Compare ADMSC SF to 3 biomimetics in accelerated aging models.