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Tissue damage key to cell reprogramming

Damaged cells will send signals to neighboring cells to reprogram them back to an embryonic state. This initiates tissue repair and could have implications for treating degenerative diseases.

Cell reprogramming does not happen exactly as we thought.

In the pages of the journal Science, a team from the Spanish National Cancer Research Centre (CNIO) has shown that tissue damage is needed for cells to go back to an embryonic state.

Cell reprogramming was discovered by Shinya Yamanaka, earning him the Nobel Prize and opening the door to regenerative medicine.

His technique is based on introducing into an adult cell the four genes known as OSKM (for the initials of the genes, OCT4, SOX2, KLF4 and MYC).

These genes revert adult cells into an embryonic-like state, known as induced pluripotent stem cells (iPSCs), which are functionally equal to embryonic stem cells.

However, there are several limitations to this process. It has a very low efficiency. And, there is the possibility for a particular type of tumour — known as teratoma – with cells of more than one germ layer. Both conditions make cell reprogramming incompatible for clinical use.

Manuel Serrano PhD, and the Tumour Suppression Group at CNIO have been working in this field for years, and their innovative approaches have led them to achieve cell reprogramming within a living organism (in this case, a mouse) in 2013. Until then, reprogramming had been only achieved using cells taken out of an organism.

Now, Serrano and his team's analysis of what happens in living tissues when OSKM reprogramming is induced, changes the idea about this technique.

"The Yamanaka genes are inefficient inducing reprogramming or pluripotency in the highly specialised cells that constitute adult tissues," explains Lluc Mosteiro PhD, who carried out most of the experimental work. Her observations indicate tissue damage plays a critical role complementing the activity of the OSKM genes.

The relationship between cell damage and cell reprogramming is mediated by interleukin-6 (IL6) a proinflammatory molecule.

Without the presence of IL6, the OSKM genes are far less efficient at inducing the reprogramming process. These findings suggest: (1) the expression of OSKM genes damages cells; (2) the cells then secrete IL6; (3) the presence of IL6 induces reprogramming of neighbouring cells.

Having identified the essential role of IL6, Serrano, Mosteiro and the rest of the team are now working on various pharmacological approaches to enhance reprogramming efficiency. Improved efficiency could help regeneration of damaged tissue even absent the Yamanaka genes. This would improve the repair capacity of tissues, and could have an obvious impact on regenerative medicine, including treatment of multiple diseases and degenerative ageing processes.

Reprogramming of differentiated cells into pluripotent cells can occur in vivo, but the mechanisms involved remain to be elucidated. Senescence is a cellular response to damage, characterized by abundant production of cytokines and other secreted factors that, together with the recruitment of inflammatory cells, result in tissue remodeling. Here, we show that in vivo expression of the reprogramming factors OCT4, SOX2, KLF4, and cMYC (OSKM) in mice leads to senescence and reprogramming, both coexisting in close proximity. Genetic and pharmacological analyses indicate that OSKM-induced senescence requires the Ink4a/Arf locus and, through the production of the cytokine interleukin-6, creates a permissive tissue environment for in vivo reprogramming. Biological conditions linked to senescence, such as tissue injury or aging, favor in vivo reprogramming by OSKM. These observations may be relevant for tissue repair.

Cristina Pantoja and Noelia Alcázar, from the Tumour Suppression Group, Maria A. Blasco and Rosa M. Marión, from the Telomeres and Telomerase Group, and several CNIO Units also participated in this study, among others.

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Nov 29, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Expression of OSKM genes in vivo, not only induce the reprogramming of a small population of cells,
but also induce damage and senescence in many other cells. Senescent cells release factors that
promote the reprogramming of neighboring cells, with IL-6 being a critical molecule.

Image Credit:
Spanish National Cancer Research Centre (CNIO)


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