Of flies, mice, and men: evolutionarily conserved tissue damage responses and aging

Abstract

Studies in flies, mice, and human models have provided a conceptual framework for how paracrine interactions between damaged cells and the surrounding tissue control tissue repair. These studies have amassed evidence for an evolutionarily conserved secretory program that regulates tissue homeostasis. This program coordinates cell survival and proliferation during tissue regeneration and repair in young animals. By virtue of chronic engagement, however, it also contributes to the age-related decline of tissue homeostasis leading to degeneration, metabolic dysfunction, and cancer. Here, we review recent studies that shed light on the nature and regulation of this evolutionarily conserved secretory program.

Figure 1. Paracrine signaling in the control of tissue regeneration, homeostasis and remodeling

(A) In the posterior midgut epithelium of Drosophila, damaged enterocytes (EC) secrete Upd cytokines upon the activation of stress signaling involving JNK and Yki. Upds activate the JAK/STAT signaling pathway of intestinal stem cells (ISCs), inducing their proliferation and generating enteroblasts (EB), which go on to differentiate into ECs or enteroendocrine (EE) cells. (B) In imaginal discs, cell competition results in the induction of apoptosis in slow growing cells (‘unfit cells’, here exemplified by cells with a lower dose of myc). Faster growing (‘fit’) cells induce apoptosis in unfit cells in a p53 and JNK-dependent manner. Apoptotic cells, in turn, promote compensatory proliferation by inducing Dpp, Wg and Upds. (C) In the mouse epiblast, fit MYC over-expressing cells induce apoptosis and engulfment of unfit cells, which in turn promote the proliferation of fit cells through paracrine signals. (D) In the mouse embryo, activation of the cell cycle inhibitor p21 can induce senescence. Senescent cells, through the SASP, fine-tune patterning and growth by supporting the survival and proliferation of neighboring fit cells.

Figure 2. Paracrine signaling promotes tissue degeneration and oncogenic phenotypes with age

(A) The Drosophila intestinal epithelium deteriorates with age, becoming populated by abnormal and dysplastic cells. These cells accumulate as a consequence of JNK-dependent ISC proliferation and defective differentiation. Different types of damage, including that caused by infection and reactive oxygen species (ROS), create an imbalance of normal signaling events, resulting in the disruption of tissue integrity due to chronic activation of stress signaling and chronic engagement of signaling processes required for tissue repair in the young epithelium (such as Upd secretion). (B) Oncogenic mutations (such as Ras^V12) in imaginal disc cell clones can also result in imbalanced paracrine signaling that ultimately causes non-autonomous overgrowth of the tissue. Ras^v12 can protect cells from JNK-induced apoptosis. These ‘undead’ cells then promote hyperplasia in the surrounding tissue by continuous secretion of Upd, Wg and Dpp. (C) In vertebrates, senescent cells induced by different stresses can promote chronic inflammation, which increases during aging due to an accumulation of senescent cells. Some SASP factors (e.g. TGF-β, IGFBP7, PAI-1, CCL2) also induce a senescence response in neighboring cells. Inflammation and the spread of senescence might be the basis for several age-related pathologies, which are characterized by a disruption of normal tissue functions. (D) Several SASP factors (MMP3, VEGF, IL6, IL8, GRO-α) can also participate in various steps in tumorigenesis, ranging from proliferation to migration and invasion. Thus, senescent cells that accumulate with age and after anti-cancer DNA damaging therapies (chemotherapy, irradiation) can create a milieu for hyperproliferation and tumor growth in the surrounding tissue.