Our body is built by an incredible variety of cell and tissue types, which develop from a single fertilized egg through embryogenesis.
Determination of the cell fate is epigenetically regulated through activation or repression of specific genes. Nuclear reprogramming is
a phenomenon that a specialized somatic cell acquires pluripotential competence, which is defined by multi-lineage differentiation,
due to reset of epigenetic memory of the somatic cell.
We found that embryonic stem (ES) cells, which have the robust capability of self-renewal with pluripotency under culture conditions,
retain the nuclear reprogramming activity as shown by cell fusion with a somatic cell (Tada et al. (2001) Curr.Biol.).
These findings have indicated the reality of direct reprogramming of somatic cell under a culture condition with factors isolated from ES cells.
Tremendously, it has been discovered that defined factors Oct4, Sox2, Klf4 and c-Myc highly expressed in ES cells are sufficient for triggering
nuclear reprogramming of somatic cells to induced pluripotent stem (iPS) cells (Takahashi and Yamanaka (2006) Cell).
It has been shown that Oct4, Sox2 and Nanog cooperatively function as key transcription regulators in the repression of somatic cell genes
and the activation of stem cell genes in pluripotent stem cells.
Reprogrammed somatic genome through cell fusion with ES cells function in cell differentiation similar to the ES genome.
Comparative analyses of epigenetic modifications of the somatic genome before and after cell fusion with ES cells demonstrated that
the nuclear reprogramming is induced at least through two steps; a) erasure of the somatic cell memory accompanied with global
chromatin de-condensation and b) acquirement of the pluripotent stem cell memory. However, the pathway from somatic cell
to pluripotent stem cell is largely in the black box.
[Aims]
1) Understanding of molecular mechanisms involved in nuclear reprogramming of somatic cells
2) Understanding of molecular function of stem cell factors in maintaining pluripotency and self-renewal
3) Development of nuclear reprogramming technologies toward clinical applications
[Importance]
The reality of personal iPS cells from individual somatic cells through nuclear reprogramming rises the great hopes on
regenerative medicine in near future. Toward realizing the regenerative medicine, further study will be required to overcome
several ethical and practical obstacles.
Understanding of the molecular mechanisms of nuclear reprogramming of somatic cells to pluripotent stem cells
will shed light on the central dogma, the succession of life.
