In situ cell reprogramming
Expression of defined transcription factors (TFs) can program or reprogram cell fate. Differentiated somatic cells can be pushed back, or reprogrammed, to a embryonic-like, pluripotent stem cell state by the overexpression of a combination of four TFs: Oct3/4, Klf4, Sox2 and cMyc. This was first achieved in vitro, generating so called induced pluripotent stem cells (iPSCs) that are invaluable research tools to study human development, disease mechanisms and toxicology, among others, and also hold promise as cell sources for tissue engineering and cell therapies.
We have participated in pioneering studies that demonstrated that cell reprogramming can also be induced in situ by forcing the expression of OKSM in vivo (Yilmazer et al, 2013, PLoS ONE; de Lázaro et al, 2014, Biomaterials). We have also demonstrated that in vivo partial cell reprogramming can enhance tissue regeneration, for example, of skeletal muscle, after severe injury (de Lázaro et al, 2019, Molecular Therapy). Most recently, we have developed transgenic mouse models to confirm that even fully differentiated, post-mitotic cells, such as cardiac myocytes, are amenable to reprogramming (de Lázaro et al, 2021, bioRxiv). Direct in vivo reprogramming offers advantages over traditional cell therapies, for example, avoiding complications related to lengthy ex vivo culture, transplantation and engraftment.
Our group takes a tissue-centric approach to in vivo reprogramming, studying not only the effects of forcing reprogramming of specific cell types, but also how external cues from the tissue microenvironment impact this process. We are also deeply involved in the path towards translation of cell reprogramming into clinically-relevant regenerative therapies through the deployment of bioengineering and nanoengineering tools.
Key Publications in this area
Irene de Lázaro, Tiara L Orejón-Sánchez, Christina M Tringides, David J Mooney*
bioRxiv (2021) https://doi.org/10.1101/2021.12.22.473302
Non-viral, tumor-free induction of transient cell reprogramming in mouse skeletal muscle to enhance tissue regeneration
Irene de Lázaro, Acelya Yilmazer, Yein Nam, Sara Qubisi, Fazilah Maizatul Abdul Razak, Hans Degens, Giulio Cossu, Kostas Kostarelos*
Molecular Therapy (2019), 27 (1): 59-75
Transient transcription factor (OSKM) expression is key towards clinical translation of in vivo cell reprogramming
Irene de Lázaro, Giulio Cossu and Kostas Kostarelos*
EMBO Mol Med (2017), 9 (6): 733-736
Açelya Yilmazer, Irene de Lázaro, Cyrill Bussy, Kostas Kostarelos*
PLoS ONE (2013): 8 (1), 1-10e54754