Essential Roles of Thyroid Hormone-Regulated Hyaluronan/CD44 Signaling in Adult Stem Cell Development During Xenopus laevis Intestinal Remodeling

Abstract

In the amphibian intestine during metamorphosis, thyroid hormone (TH) induces some larval epithelial cells to dedifferentiate into stem cells, which generate the adult epithelium analogous to the mammalian intestinal epithelium. We have previously shown that the canonical Wnt signaling pathway is involved in adult epithelial development in the Xenopus laevis intestine. To understand the function of this pathway more precisely, we here focused on CD44, a major Wnt target, which has been identified as a TH response gene in the X. laevis intestine. Our in situ hybridization analysis indicated that CD44 mRNA is detectable in adult epithelial primordia consisting of the adult stem/progenitor cells and is strongly expressed in the connective tissue (CT) cells surrounding them. Interestingly, when the expression of CD44 mRNA is the highest, hyaluronan (HA), a principle ligand of CD44, is newly synthesized and becomes most abundantly distributed in the CT just beneath the adult epithelial primordia that are actively proliferating. Thereafter, as the adult primordia differentiate into the simple columnar epithelium, the expression of CD44 mRNA is gradually downregulated. More importantly, using organ cultures of the X. laevis tadpole intestine in the presence of TH, we have experimentally shown that inhibition of HA synthesis by 4-methylumbelliferone suppresses development of not only the CT but also the epithelial stem cells, resulting in failure to generate the AE. Our findings strongly suggest that TH-upregulated HA/CD44 signaling plays an essential role in formation of the intestinal stem cell niche during vertebrate postembryonic development. Stem Cells 2017;35:2175-2183.

Diverse Roles for Hyaluronan and Hyaluronan Receptors in the Developing and Adult Nervous System

“…CD44- and HA-dependent regulation of adult neurogenesis may explain why CD44 null animals experience learning and memory defects [ 64 ]. These findings are consistent with studies showing that CD44 has functions in other embryonic and adult stem/progenitor cell populations [ 148 , 149 ].…”

Prognostic Value of CD44 and Its Isoforms in Advanced Cancer: A Systematic Meta-Analysis With Trial Sequential Analysis

“…To date, CD44s remains the most commonly reported isoform in cancer, but the other CD44 variants (CD44v) are also correlated with neoplasia and metastasis in some cancers (52) CD44 is a frequently observed CSC marker in solid tumors, and CD44 was revealed to be a major Wnt target, involved in the Ras-Raf-Mek-Erk-Cyclin D1 pathway, phosphoinositide 3-kinase (PI3K)-Akt signaling, and the Wnt pathway, as well as stimulating EMT, which promotes tumor invasion, progression and metastasis (53–55). Some studies suggest that expression of total CD44 may be correlated with distant metastasis, tumor recurrence and a worse prognosis (19, 56, 57).…”

Deficiency of type 2 iodo‐ thyronine deiodinase reduces necroptosis activity and oxidative stress responses in retinas of Leber congenital amaurosis model mice

“…This presumption is also supported by our findings that showed reduced expression of the TH receptor-target genes in Rpe65 2/2 /Nrl 2/2 /Dio2 +/2 retinas, relative to that in Rpe65 2/2 /Nrl 2/2 retinas. The genes Pepck, Pdk4, Cd44 (encoding CD44), and Hes5 (encoding Hes family bHLH transcription factor 5) are the known TH receptor-target genes (54,(63)(64)(65). Expression of these genes was significantly reduced in Rpe65 2/2 /Nrl 2/2 /Dio2 +/2 retinas, relative to that in Rpe65 2/2 /Nrl 2/2 retinas (Fig.…”