Messenger functions of cell death during development and homeostasis

Abstract

In our human society, would you not want to know if your neighbor suddenly passed away? Tissues and cells are not that different. Cell death is an inevitable part of tissue homeostasis and comes in different flavors that can either be a consequence of an injury or a regulated phenomenon (such as programed cell death). Historically, cell death was viewed as a way to discard cells, without functional consequences. Today, this view has evolved and recognizes an extra layer of complexity: dying cells can provide physical or chemical signals to notify their neighbors. Like any type of communication, signals can only be read if surrounding tissues have evolved to recognize them and functionally adapt. This short review aims to provide a summary of recent work interrogating the messenger functions and consequences of cell death in various model organisms.

Keywords: apoptosis; cell death; cell homeostasis; developmental biology; purinergic signaling.

Figure 1.. Messenger functions of apoptotic cell death.

Graphical summary of the most recent discoveries linking apoptotic cell death to signaling cascade in neighboring cells. Apoptotic cell death can (1) promote release of inflammatory molecules (top left), (2) induce proliferation (top right), (3) drive various signaling pathways mediated by metabolites release (bottom left) and (4) stimulate a refractory period against apoptosis (bottom right). MAPK-ATF, MAPK signaling-responsive activating transcription factors; PSC, pluripotent stem cell; EMT, epithelial-to-mesenchymal transition; LPC, lysophosphatidylcholine.

Figure 2.. Apoptosis-dependent nucleotide signaling during cardiac mesoderm lineage commitment.

Upon differentiation (CHIR addition in RPMI/B27 (- insulin)), a subpopulation of human induced pluripotent stem cells (iPSCs) undergo apoptosis. Pannexin-1 C-term gets cleaved following caspases activation, leading to a constitutively active channel. Among other metabolites, ATP and UTP leak out from apoptotic cells and bind to purinergic P2Y2 receptor at the surface of the surviving population. This nucleotide signaling, in complement to WNT activation, drives the expression of primitive streak (EOMES), mesoderm (Bra/T) and cardiac progenitor markers (MESP1). Cells receiving this signal can undergo epithelial-to-mesenchymal transition, regulated by Snail/Slug. In fine, cells will acquire cardiac markers, such as cardiac troponin T (cTnT).