Pathological in situ reprogramming of somatic cells by the unfolded protein response

In response to tissue injuries, terminally differentiated cells are reprogrammed to undergo dedifferentiation to gain mitogenic and metabolic properties. The dedifferentiated cells acquire an immature phenotype, proliferate actively, produce abundant extracellular matrix, and recruit circulating leukocytes via secretion of chemokines, contributing to tissue repair and/or fibrosis. However, this remodeling process is self-limiting, and in the later phase, the activated, dedifferentiated cells are reprogrammed to redifferentiate into a mature, quiescent phenotype. Currently, molecular mechanisms underlying this bidirectional pathological reprogramming remain elusive. It is known that the unfolded protein response (UPR) is induced at local tissues under pathological situations and affects cellular fate-survival or death. It is also known that the UPR is involved in cell differentiation and organogenesis during embryonic development. In this review, we describe a hypothesis for regulatory roles of the UPR in the pathological reprogramming of somatic cells (ie, cellular dedifferentiation and redifferentiation at the sites of injury).