Mature cells can be converted into stem cells without genetic modification

Recent research conducted by Professor G.V. Shivashankar from Singapore, showed that mature cells can be reprogrammed into stem cells without direct genetic modification, but only by limiting the space in which they are divided. The findings are published in Proceedings of the National Academy of Sciences (PNAS).

Stem cells are the basis for the development of all specialized cells and tissues of the body. Researchers from the Mechanobiology Institute (MBI) at the National University of Singapore (NUS) and the FIRC Institute of Molecular Oncology (IFOM) in Italy have found that space-limited mature cells lose their specialized characteristics the sixth day and completely return to the state of the stem on the tenth day.

“Our breakthrough findings will usher in a new generation of stem cell technologies for tissue engineering and regenerative medicine that may overcome the negative effects of geonomic manipulation”,

– said Prof Shivashankar.

More than a decade ago, scientists first showed that mature cells can be reprogrammed into pluripotent stem cells that can develop into any type of body cells.

In these early experiments, researchers genetically modified adult specialized cells, introducing factors that reset their genomic programs, reversing their development and returning to an undifferentiated (unspecialized) state.

The resultant lab-made cells, known as induced pluripotent stem cells (iPSCs), can then be programmed into different pathways for use in tissue repair, drug discovery, and even to grow new organs for transplant. Another important advantage of iPSC is that you do not need to use embryos to obtain them.

However, the main obstacle for the clinical use of iPSC remains their predisposition to malignant transformation after being introduced into the body. And the main reason is precisely the interference in their genome from the outside. To solve this problem, researchers decided to understand how the differentiation and growth of stem cells in the body is regulated. In particular, how cells naturally return to an immature state, and also convert into another cell type, during development, or in tissue maintenance.

The team led by Shivashankar worked with fibroblasts – mature cells that are located in connective tissue, for example, in tendons and ligaments.

Scientists have limited the growth zone of fibroblasts to a rectangular region, as a result of which the cells quickly took the form of a substrate.

The experiments conducted earlier by the Shivashankar group showed that the cells react to the physical properties of the environment and transmit this information to the nucleus, where the DNA and genome programs change in accordance with the received data.

In this study, fibroblasts, as a result of the restriction of growth space, began to form spherical clusters on the 10th day of cultivation. Genetic analysis showed that the specific characteristics of chromatin inherent in mature cells were lost by the sixth day.

By the tenth day, scientists claim, the cells expressed genes that are typically characteristic of embryonic stem cells and iPSCs. Researchers came to the conclusion that by limiting mature fibroblasts in space for a long time, they can be turned into pluripotent stem cells.

To confirm the reprogramming of fibroblasts in to stem cells, the researchers successfully directed their differentiation into two different types of specialized cells. Some cells were also directed back into fibroblasts.

The data obtained in the course of the study on the effect of transientgeometric constraints reflect that cells can be exposed to in the body. Thus, the surrounding structure plays an important role in the formation of functional tissues and organs in embryonic development.

Also, if tissue is damaged due to injury or disease, cells “feel” sudden changes in their environment and are activated to regenerate the site. For these purposes, mature cells can return to the pluripotent state in order to differentiate into specialized cells necessary for tissue repair.

“While it is well established that confining stem cells to defined geometric patterns and substrate properties can direct their differentiation into specialised cells, this study shows for the first time that mechanical cues can reset the genomic programmes of mature cells and return them to a pluripotent state”,

– Prof Shivashankar explained.

“The use of geometric constraints to reprogramed mature cells may better reflect the process occurring naturally within the body. More importantly, our findings allow researchers to generate stem cells from mature cells with high efficiency and without genetically modifying them”,

– he added.