Dedifferentiation of Adult Monkey Sertoli Cells through Activation of Extracellularly Regulated Kinase 1/2 Induced by Heat Treatment

Abstract

Sertoli cells play a key role in triggering and regulating the process of spermatogenesis. Failure of a Sertoli cell to mature functionally will presumably render it incapable of supporting germ cell survival and development that appeared after puberty. Expression of cytokeratin 18 (ck-18) intermediate filaments indicates a state of undifferentiation usually observed in Sertoli cells of prepubertal testis. In this study we demonstrated that local testicular heat treatment of adult monkey with water at 43 C for 30 min once daily for 2 consecutive days was capable of activating reexpression of ck-18 in Sertoli cells, which was coincident with activation of ERK1/2 and Akt kinases. Using primary Sertoli cell culture isolated from adult monkey testis, we further confirmed that the heat treatment of the cells at 43 C could also induce ck-18 reexpression, which was similar to the in vivo treatment. ERK MAPK was also induced by the heat treatment in a time- and protein kinase A (PKA)-dependent manner. After blocking the ERK MAPK signaling pathway, an inhibition of ck-18 expression in the cultured Sertoli cells was observed, and this inhibitory effect was also detected by blocking the PKA activation. However, ck-18 activation in Sertoli cells remained unaltered when the phosphatidylinositol 3-kinase/Akt pathway was blocked. In conclusion, the heat treatment of adult monkey Sertoli cells are capable of inducing a reversible change in the Sertoli cells from an adult differentiated state to an immature-like dedifferentiated state through PKA-ERK MAPK-dependent pathways but not via the phosphatidylinositol 3-kinase/Akt pathway.

Biological Functions of Cytokeratin 18 in Cancer

“…In a study with adult monkeys, Zhang and colleagues (28) showed that local testicular heat treatment was able to activate the reexpression of CK18 in Sertoli cells, which was coincident with activation of extracellular signal-regulated kinase (ERK)1/2 and Akt kinases. After blocking the ERK mitogen-activated protein kinase (MAPK) signaling pathway, they observed an inhibition of CK18 expression, and they also detected this inhibitory effect by blocking protein kinase A (PKA) activation.…”

“…However, CK18 activation remained unaltered when the PI3K/Akt pathway was blocked. Zhang and colleagues (28) concluded that the heat treatment was able to induce a reversible change in the Sertoli cells from an adult differentiated state to an immature-like dedifferentiated state through PKA-ERK MAPK-dependent pathways, but not via the PI3K/Akt pathway. In another study, Gilbert and colleagues (29) showed that inhibition of ERK1/2 activation sensitized wild-type but not K8-null mouse hepatocytes to apoptosis, and a much weaker ERK1/2 activation occurred in CK8-null hepatocytes.…”

“…The cross-linking functions of plectin help organize the cytoskeleton into a stable meshwork that is important for maintaining uniformity of cell size and shape. In one study (30), expression of CK18 was shown to be downregulated by suppression of plectin protein, and cytokeratin networks (12,14,(22)(23)(24) and of ERK1/2 in the ERK MAPK pathway (28,29), and regulation of CK18 by Wnt is involved in Akt activation (26,27). Questions regarding the PI3K/Akt and Wnt pathways, and whether CK18 functions as the regulator in these three pathways require further investigation.…”

Dedifferentiation: A New Approach in Stem Cell Research

“…The heat treatment of the primary Sertoli cell culture isolated from the adult monkey testis at 43°C could also induce CK-18 reexpression. These results from in vivo and in vitro experiments demonstrated that heat treatment of adult monkey Sertoli cells was capable of inducing a reversible change in the Sertoli cells from an adult differentiated state to an immature dedifferentiated state (Zhang et al 2006). …”

Dedifferentiation of Human Epidermal Keratinocytes Induced by UV In Vitro

“…: +86 1068210077; Fax: +86 10 68989955; E-mail: fuxiaobing@vip.sina.com ies suggest that dedifferentiation may be possible in mammalian system. It was reported that pancreatic cells, 1) renal epithelial cells, 2) retinal cells, 3) myoblasts, 4) neurons, 5) and germ cells 6) have the potential of dedifferentiation in response to appropriate signals or factors. Obviously, commitment to terminal differentiation is not an irreversible process.…”