RESUMEN
Aging is associated with loss of proliferation of the insulin-secreting ß-cell, a possible contributing factor to the increased prevalence of type 2 diabetes in the elderly. Our group previously discovered that moderate endoplasmic reticulum (ER) stress occurring during glucose exposure increases the adaptive ß-cell proliferation response. Specifically, the ATF6α arm of the tripartite Unfolded Protein Response (UPR) promotes ß-cell replication in glucose excess conditions. We hypothesized that ß-cells from older mice have reduced proliferation due to aberrant UPR signaling or an impaired proliferative response to ER stress or ATF6α activation. To investigate, young and old mouse islet cells were exposed to high glucose with low-dose thapsigargin or activation of overexpressed ATF6α, and ß-cell proliferation was quantified by BrdU incorporation. UPR pathway activation was compared by qPCR of target genes and semi-quantitative Xbp1 splicing assay. Intriguingly, although old ß-cells had reduced proliferation in high glucose compared to young ß-cells, UPR activation and induction of proliferation in response to low-dose thapsigargin or ATF6α activation in high glucose were largely similar between young and old. These results suggest that loss of UPR-led adaptive proliferation does not explain the reduced cell cycle entry in old ß-cells, and raise the exciting possibility that future therapies that engage adaptive UPR could increase ß-cell number through proliferation even in older individuals.
Asunto(s)
Envejecimiento/fisiología , Proliferación Celular , Estrés del Retículo Endoplásmico/fisiología , Células Secretoras de Insulina/fisiología , Envejecimiento/metabolismo , Animales , Células Cultivadas , Retículo Endoplásmico/metabolismo , Femenino , Células Secretoras de Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND: A growing body of literature suggests the cell-intrinsic activity of Atf6α during ER stress responses has implications for tissue cell number during growth and development, as well as in adult biology and tumorigenesis [1]. This concept is important, linking the cellular processes of secretory protein synthesis and endoplasmic reticulum stress response with functional tissue capacity and organ size. However, the field contains conflicting observations, especially notable in secretory cell types like the pancreatic beta cell. SCOPE OF REVIEW: Here we summarize current knowledge of the basic biology of Atf6α, along with the pleiotropic roles Atf6α plays in cell life and death decisions and possible explanations for conflicting observations. We include studies investigating the roles of Atf6α in cell survival, death and proliferation using well-controlled methodology and specific validated outcome measures, with a focus on endocrine and metabolic tissues when information was available. MAJOR CONCLUSIONS: The net outcome of Atf6α on cell survival and cell death depends on cell type and growth conditions, the presence and degree of ER stress, and the duration and intensity of Atf6α activation. It is unquestioned that Atf6α activity influences the cell fate decision between survival and death, although opposite directions of this outcome are reported in different contexts. Atf6α can also trigger cell cycle activity to expand tissue cell number through proliferation. Much work remains to be done to clarify the many gaps in understanding in this important emerging field.