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Collagen IV differentially regulates planarian stem cell potency and lineage progression

Andy Chan,Sophia Ma,Bret J. Pearson,D. Chan

Published 2021 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Comprehensive assessment of matrisome genes identified collagen IV as one of the many extracellular matrix (ECM) proteins regulating the stem cell pool in planarian tissue homeostasis and regeneration. While collagen IV has been shown to be involved in stem cell biology, our finding links it to pluripotent stem cells in vivo, including self-renewal and differentiation into tissue-specific progenitors. We show a link between the ECM niches in the parenchyma/gut region and EGF/neuregulin-secreting neurons, thus providing mechanistic insight into interactions between cell niches. The conservation of basement membranes between planarian and mammalian gut niches suggests a similar interplay may exist in the mammalian systems, worthy of further investigation. The extracellular matrix (ECM) provides a precise physical and molecular environment for cell maintenance, self-renewal, and differentiation in the stem cell niche. However, the nature and organization of the ECM niche is not well understood. The adult freshwater planarian Schmidtea mediterranea maintains a large population of multipotent stem cells (neoblasts), presenting an ideal model to study the role of the ECM niche in stem cell regulation. Here we tested the function of 165 planarian homologs of ECM and ECM-related genes in neoblast regulation. We identified the collagen gene family as one with differential effects in promoting or suppressing proliferation of neoblasts. col4-1, encoding a type IV collagen α-chain, had the strongest effect. RNA interference (RNAi) of col4-1 impaired tissue maintenance and regeneration, causing tissue regression. Finally, we provide evidence for an interaction between type IV collagen, the discoidin domain receptor, and neuregulin-7 (NRG-7), which constitutes a mechanism to regulate the balance of symmetric and asymmetric division of neoblasts via the NRG-7/EGFR pathway.

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