Cell death induced autophagy contributes to terminal differentiation of skin and skin appendages

Abstract

In the adult mammalian skin, cells are constantly renewing, differentiating and moving upward, to finally die in a yet not fully understood manner. Here, we provide evidence that macroautophagy/autophagy has a dual role in the skin. In addition to its known catabolic protective role as an evolutionary conserved upstream regulator of lysosomal degradation, we show that autophagy induced cell death (CDA) occurs in epithelial lineage-derived organs, such as the inter-follicular epidermis, the sebaceous-and the Harderian gland. By utilizing GFP-LC3 transgenic and ATG7-deficient mice, we show that CDA is initiated during terminal differentiation at a stage when the cells have become highly resistant to apoptosis. In these transitional cells, the Golgi compartment expands, which accounts for the formation of primary lysosomes, and the nucleus starts to condense. During CDA a burst of autophagosome formation is observed, first the endoplasmic reticulum (ER) is phagocytosed followed by autophagy of the nucleus. By this selective form of cell death, most of the cytoplasmic organelles are degraded, but structural proteins remain intact. In the absence of autophagy, consequently, parts of the ER, ribosomes, and chromatin remain. A burst of autophagy was stochastically observed in single cells of the epidermis and collectively in larger areas of ductal cells, arguing for a coordinated induction. We conclude that autophagy is an integral part of cell death in keratinocyte lineage cells and participates in their terminal cell fate.

Live imaging of alterations in cellular morphology and organelles during cornification using an epidermal equivalent model

“…This finding supports the notion that mitochondria are partly degraded by autophagy in granular cells before the start of morphological change. It is debatable, however, whether autophagy itself is essential for cornification in the physiological epidermis 10,[55][56][57][58][59][60][61] . Factors that influence mitochondrial conditions, such as ROS and ER stress, may participate in preparing for cornification.…”

Monocyte Chemotactic Protein-Induced Protein 1 (MCPIP-1): A Key Player of Host Defense and Immune Regulation

“…MCPIP-1 was first described as a transcriptional activator owing to the structural feature of a potential DNA binding zinc finger domain (9). Subsequent studies indicate that MCPIP is localized to both the cytoplasmic and nuclear compartments, depending on the distinct functions it plays in different cell types (11,37,38). Mutational analysis of MCPIP-1 has identified the two regions of the primary structure that are critical for its biological activity (12,(39)(40)(41).…”

27TH Fondation René Touraine Annual SCIENTIFIC MEETING 2019

“…Let us wrap up this eclectic dash through the most recent hair research literature with a deep bow to the pioneers of autophagy, Christian de Duve and Yoshinori Ohsumi, [75,76] since the importance of their autophagy-related concepts for skin and skin appendage biology is only now beginning to get appreciated. [77,78] Given that the role of autophagy in human physiology remains poorly understood, we hypothesized that the organ culture of cycling human scalp HFs [19] may offer a good model for studying and interrogating autophagy in a human (mini)organ. anti-hair loss product containing spermidine (this prominent "senolytic" polyamine is known to potently stimulate autophagic flux in many systems and to prolong anagen in human HFs [79] ) this significantly upregulates intrafollicular autophagy.…”

“…A most recent transcriptional analysis of AA skin biopsies suggests that abnormalities in autophagy may also play a role in the pathobiology of AA. [80] This further encourages one to systematically explore both, the role of autophagy in skin health and disease [77,78] and novel therapeutic strategies to target it.…”

“…Let us wrap up this eclectic dash through the most recent hair research literature with a deep bow to the pioneers of autophagy, Christian de Duve and Yoshinori Ohsumi, since the importance of their autophagy‐related concepts for skin and skin appendage biology is only now beginning to get appreciated . Given that the role of autophagy in human physiology remains poorly understood, we hypothesized that the organ culture of cycling human scalp HFs may offer a good model for studying and interrogating autophagy in a human (mini)organ.…”