Effects of inflammation on stem cells: together they strive?

Abstract

Inflammation entails a complex set of defense mechanisms acting in concert to restore the homeostatic balance in organisms after damage or pathogen invasion. This immune response consists of the activity of various immune cells in a highly complex manner. Inflammation is a double-edged sword as it is reported to have both detrimental and beneficial consequences. In this review, we discuss the effects of inflammation on stem cell activity, focusing primarily on neural stem/progenitor cells in mammals and zebrafish. We also give a brief overview of the effects of inflammation on other stem cell compartments, exemplifying the positive and negative role of inflammation on stemness. The majority of the chronic diseases involve an unremitting phase of inflammation due to improper resolution of the initial pro-inflammatory response that impinges on the stem cell behavior. Thus, understanding the mechanisms of crosstalk between the inflammatory milieu and tissue-resident stem cells is an important basis for clinical efforts. Not only is it important to understand the effect of inflammation on stem cell activity for further defining the etiology of the diseases, but also better mechanistic understanding is essential to design regenerative therapies that aim at micromanipulating the inflammatory milieu to offset the negative effects and maximize the beneficial outcomes.

Keywords: disease; inflammation; neural stem cell; proliferation; regeneration.

© 2015 The Authors.

Figures

Figure 1

A simplified generic scheme of initiation and resolution of inflammation in six steps 1) A tissue when compromised during its homeostatic state initiates inflammation programs, through damage cues (such as intracellular content, apoptosis and cytokines). 2) Breach of homeostasis triggers the morphological and functional transformation of the resident macrophages (green). 3) Acute inflammation is initiated upon secretion of several pro-inflammatory cytokines and chemokines such as TNF-α, IL-1β, IL-6 and MCP-1. Complement system is also activated. 4) This process calls for peripheral immune cells, and recruited immune cells potentiate the inflammation by secreting more pro-inflammatory factors. 5) The immune cells also partake in active resolution of inflammation through secretion of anti-inflammatory factors such as IL-4, IL-10, C5a, IFN-γ, TGF-β and NO. A stem/progenitor cell undergoes the influence of the dynamic inflammatory milieu. The final outcome on the tissue manifests depending on the context.

Figure 2

Mammalian neural stem/progenitor cells are generally negatively affected by inflammation Signaling cascades through Cystlr1, IFN-α and IFN-γ receptors and Cr2, which are expressed by neural stem/progenitor cells (orange, NSPC), as well as macrophage-derived TNF-α and IL-1β, suppress self-renewal. IL-10 secreted by monocytes blocks neuronal differentiation, while CCR2 and MCP-1 hamper neuronal survival, migration and maturation. T cells secrete BDNF to positively regulate neurogenesis from stem cells through its receptor TrkB and intracellular cascades of phosphorylated Akt and survivin. CXCR4/SDF1 chemokine signaling is required for directed migration of neural stem/progenitor cells and neurons.

Figure 3

Inflammation promotes neurogenesis and regeneration in zebrafish In zebrafish, inflammation elicited by immune cells leads to secretion of leukotriene C4 (LTC4, green circles), which bind to its receptor Cystlr1 on neural stem/progenitor cell (NSPC). LTC4/Cystlr1 signaling leads to transcriptional activation of zinc-finger transcription factor Gata3, which is a key molecule that promotes proliferation and regenerative neurogenesis. Chemokine signaling through Cxcr5 is also required for differentiation of proliferating NSPCs into neurons.