Dysregulation of the B mi‐1/p16 ^Ink4a pathway provokes an aging‐associated decline of submandibular gland function

Abstract

Bmi-1 prevents stem cell aging, at least partly, by blocking expression of the cyclin-dependent kinase inhibitor p16Ink4a. Therefore, dysregulation of the Bmi-1/p16Ink4a pathway is considered key to the loss of tissue homeostasis and development of associated degenerative diseases during aging. However, because Bmi-1 knockout (KO) mice die within 20 weeks after birth, it is difficult to determine exactly where and when dysregulation of the Bmi-1/p16Ink4a pathway occurs during aging in vivo. Using real-time in vivo imaging of p16Ink4a expression in Bmi-1-KO mice, we uncovered a novel function of the Bmi-1/p16Ink4a pathway in controlling homeostasis of the submandibular glands (SMGs), which secrete saliva into the oral cavity. This pathway is dysregulated during aging in vivo, leading to induction of p16Ink4a expression and subsequent declined SMG function. These findings will advance our understanding of the molecular mechanisms underlying the aging-related decline of SMG function and associated salivary gland hypofunction, which is particularly problematic among the elderly.

The Polycomb Group Protein Pcgf1 Is Dispensable in Zebrafish but Involved in Early Growth and Aging

“…Such a link between epigenetics and aging has also been reported for other PCGF family members. In particular, Bmi1 -deficient mice exhibit postnatal defects in the self-renewal of adult stem cells and the aging-associated dysregulation of the Bmi1/p16 Ink4a pathway may account for failures in tissue repair in aging [ 59 – 62 ]. Interestingly, a genome-wide gain-of-function genetic screen in mouse embryonic stem (ES) cells also identifies Pcgf1 as a factor able to promote the expression of the ES cell pluripotency markers and able to partially rescue ES cell growth in the absence of leukemia inhibitory factor (LIF) [ 63 ].…”

Similar ex vivo expansion and post-irradiation regenerative potential of juvenile and aged salivary gland stem cells

“…Recently, Yamakoshi and colleagues [19] reported age-related dysregulation of Bmi-1/p16 Ink4a pathway and a subsequent decline of stem or progenitor cell function in submandibular glands. While extending the current understanding of the molecular mechanisms underlying the aging-related decline of SMG function, the study [19] did not focus on refined populations of SGSCs. Due to widespread variation in attempts to characterize aging it is of vital importance to conduct analysis in purified cell populations.…”

Sirt1 Promotes Osteogenic Differentiation and Increases Alveolar Bone Mass via Bmi1 Activation in Mice

“…Bmi1 plays an important but complex role in the self‐renewal and differentiation of MSCs. Bmi1 and Sirt1 are polycomb group proteins; they have common downstream target genes such as p16, p19, and p53 . Bmi1‐deficient mice (Bmi1 −/− ) display defects in the hematopoietic, nervous, and skeletal systems .…”