Abstract
Intestinal epithelial cells (IECs) are regenerated continuously from intestinal stem cells (ISCs) near the base of intestinal crypts in order to maintain homeostasis and structural integrity of intestinal epithelium. Epidermal growth factor (EGF) is thought to be important to drive the proliferation and differentiation of IECs from ISCs, it remains unknown whether other growth factors or lipid mediators are also important for such regulation, however. Here we show that lysophosphatidic acid (LPA), instead of EGF, robustly promoted the development of intestinal organoids prepared from the mouse small intestine. Indeed, LPA exhibited the proliferative activity of IECs as well as induction of differentiation of IECs into goblet cells, Paneth cells, and enteroendocrine cells in intestinal organoids. Inhibitors for LPA receptor 1 markedly suppressed the LPA-promoted development of intestinal organoids. LPA also promoted the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in intestinal organoids, whereas inhibition of mitogen-activated protein kinase/ERK kinase (MEK) 1/2 significantly suppressed the development of, as well as the proliferative activity and differentiation of, intestinal organoids in response to LPA. Our results thus suggest that LPA is a key factor that drives the proliferation and differentiation of IECs.
Highlights
In the intestine, intestinal epithelial cells (IECs) are regenerated continuously throughout adulthood from intestinal stem cells (ISCs) at the base of intestinal crypts [1, 2]
hepatocyte growth factor (HGF) and insulin-like growth factor-1 (IGF-1), both of which effects are thought to be mediated by their receptor tyrosine kinase, promoted the development of intestinal organoids, their effect was much smaller than that of Epidermal growth factor (EGF), (Fig 1A–1C)
lysophosphatidic acid (LPA) promoted the development of intestinal organoids (Fig 1A–1C); the effect was smaller than that apparent for EGF, but it was significantly larger than other factors tested (Fig 1A–1C)
Summary
Intestinal epithelial cells (IECs) are regenerated continuously throughout adulthood from intestinal stem cells (ISCs) at the base of intestinal crypts [1, 2]. ISCs selfrenew and generate transient amplifying (TA) cells, which are highly proliferative progenies [1, 2]. The TA cells localize above the stem cell niche, divide rapidly, and differentiate into the various IECs such as absorptive enterocytes, mucin-producing goblet cells, peptide hormone– secreting enteroendocrine cells, and antimicrobial peptide–producing Paneth cells. IECs, except Paneth cells, mature and migrate up the crypt toward the tip of intestinal villi. Paneth cells travel down to the base of intestinal crypts and contribute to the stem cell niche by secreting Wnt ligands such as Wnt3 [2, 3].
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