Redefining stem cell technologies

11 July 2018 | Research
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When a mature cell is confined to a rectangular substrate and allowed to grow over 10 days, specific genomic markers are lost and the resulting cluster expresses genes normally associated with embryonic stem cells and iPSCs

Professor GV Shivashankar of the NUS Mechanobiology Institute and Italy’s FIRC Institute of Molecular Oncology and his team of researchers have made a breakthrough discovery which may allow researchers to generate stem cells from mature cells with high efficiency and without the need to genetically modify them.

They revealed that mature cells can be reprogrammed into redeployable stem cells by simply confining the mature cells to a defined area of growth for an extended period of time – 10 days to be exact.

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 genomic manipulation.

Over a decade ago, scientists first showed that mature cells can be reprogrammed in the laboratory to become pluripotent stem cells that are capable of being developed into any cell type in the body — an alternative to harvesting stem cells from embryos. In those early studies, researchers introduced external factors that reset the genomic programmes of mature cells to return them to an undifferentiated or unspecialised state. These lab-made cells, known as induced pluripotent stem cells (iPSCs), can then be programmed into different cell types for use in tissue repair, drug discovery and even growing new organs for transplants.

However, a major obstacle is the tendency of specialised cells developed from iPSCs to form tumours after they are introduced into the body. To understand why this occurs, researchers turned their attention to understanding how stem cell differentiation and growth is regulated in the body, and in particular, how cells naturally revert to an immature stem cell-like state or convert to another cell type during development or in tissue maintenance.

Prof Shivashankar’s team experimented on fibroblast cells — a type of mature cell found in connective tissues such as tendons and ligaments. By controlling the surface or medium that the cells are attached to, they confined fibroblast cells to rectangular areas and grew the cells over 10 days until they formed spherical clusters. Genetic analysis of these cluster cells revealed that specific genomic markers normally associated with the mature cells were lost by the sixth day. By the 10th day, the cells expressed genes normally associated with embryonic stem cells and iPSCs which can be reprogrammed and redeployed.

The physical parameters used in the study are reflective of the transient geometric constraints that cells are often exposed to in the body, for instance during the formation of functional tissues and organs or through injury or disease. It proves for the first time that mechanical cues can reset the genomic programmes of mature cells and return them to a pluripotent state.

“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 genomic manipulation,” said Prof Shivashankar.

The team’s findings were published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) in May.

See press release