Conditional telomerase induction causes proliferation of hair follicle stem cells

Abstract

TERT, the protein component of telomerase 1,2 , serves to maintain telomere function through the de novo addition of telomere repeats to chromosome ends and is reactivated in 90% of human cancers. In normal tissues, TERT is expressed in stem cells and in progenitor cells 3 , but its role in these compartments is not fully understood. Here, we show that conditional transgenic induction of TERT in mouse skin epithelium causes a rapid transition from telogen, the resting phase of the hair follicle cycle, to anagen, the active phase, thereby facilitating robust hair growth. TERT overexpression promotes this developmental transition by causing proliferation of quiescent, multipotent stem cells in the hair follicle bulge region. This new function for TERT does not require the telomerase RNA component (TERC), which encodes the template for telomere addition, and therefore operates through a novel mechanism independent of its activity in synthesizing telomere repeats. These data indicate that, in addition to its established role in extending telomeres, TERT can promote proliferation of resting stem cells through a non-canonical pathway. Keywords telomerase; telomere; stem cell; hair follicle; epidermis In stem cell and progenitor cell compartments 3-5 , TERT serves an important role in keeping telomeres sufficiently long and stable to prevent the adverse consequences of dysfunctional telomeres on cell viability and chromosomal stability 6-8 . However, the need for expression of TERT in tissue stem cells and progenitor cells with long telomeres is less clear, especially in laboratory mice, whose telomeres are significantly longer than those of humans (40-60kb vs. 5-15kb). Moreover, recent findings indicate that TERT promotes tumor development even in settings of ample telomere reserve, although the mechanisms underlying these telomere length-independent activities of TERT remain unclear 9-13 . We therefore hypothesized that TERT may exert effects in stem cell and progenitor cell compartments that could explain both its regulation during lineage development and its poorly understood telomere lengthindependent activities.To test this hypothesis, we turned to the mammalian hair follicle, an organ that harbors tightly regulated multipotent stem cells and that cycles between telogen and anagen 14 . Initiation of a new anagen cycle depends upon activation of a small number of quiescent stem cells that reside

Introduction of SV40ER and hTERT into mammospheres generates breast cancer cells with stem cell properties

“…In addition, the ST antigen has been shown to activate Notch, Hedgehog and Wnt pathways (Ali-Seyed et al, 2006) all of which are associated with stem cell self-renewal as well as breast carcinogenesis (Liu et al, 2005). Furthermore, overexpression of telomerase is also known to enhance proliferation of adult stem cells (Sarin et al, 2005). Thus, the introduced oncogenes are likely to have contributed to the long-term stemness properties of NBLE cells.…”

Epigenetic regulation of aging stem cells

“…In mice, deletion of Terc results in decreased lifespan after several generations (Rudolph et al, 1999), implicating telomerase components as longevity factors. Interestingly, distinct from its action in telomere maintenance, TERT regulates the mobilization and proliferation of epidermal stem cells in the hair follicle (Flores et al, 2005;Sarin et al, 2005). Consistent with its prominent role in stem cell proliferation independent of its reverse transcriptase activity, TERT is a pivotal component of the transcriptional complex downstream of WNT signaling (Choi et al, 2008;Park et al, 2009).…”

Somatic stem cells and the origin of cancer

“…Together, these data point out to a role of telomeres in the regulation of HSC homeostasis 102 . Two recent studies investigated the effects of telomerase and telomere length on epidermal stem cell behaviour 103,104 . Using different constitutive and inducible transgenic mouse models, authors demonstrated that telomere length and telomerase activity are independent determinants of the mobilization efficiency and proliferative capacity of epidermal stem cells.…”