Collagen IV differentially regulates planarian stem cell potency and lineage progression

Abstract

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.

Intestine-enrichedapolipoprotein borthologs are required for stem cell differentiation and regeneration in planarians

“…In planarians, specification likely begins during S-phase, because expression of fate-specific transcription factors is significantly higher in S/G2/M neoblasts than in G1 neoblasts 57,62 . Intriguingly, inhibition of other planarian genes required for differentiation (e.g., the transcription factor mex3-1, the extracellular matrix component collagen4-1, and the transcriptional co-activating protein cbp-3) also cause increases in neoblast numbers in vivo 52,[63][64][65] . Furthermore, knockdown of exocyst component 3 (exoc3), a negative regulator of pluripotency whose mammalian homolog Tnfaip3 promotes embryonic stem cell differentiation, causes expansion of the S/G2/M (X1) neoblast fraction 66 .…”

“…Lastly, we find that apob inhibition dysregulated genes associated with muscle differentiation and function (Supplementary Data 5). In planarians, muscle cells not only secrete axial polarity cues, but also serve a fibroblast-like role by secreting most components of the extracellular matrix, whose functions are required to both spatially restrict the stem cell compartment, and modulate proliferation and differentiation 63, 88, 89 . apob RNAi causes moderate downregulation of most fibrillar collagens, as well as the basement membrane collagen4-1, which promotes differentiation 63 (Supplementary Data 4 and 5).…”

Decoding Stem Cells: An Overview on Planarian Stem Cell Heterogeneity and Lineage Progression

“…In particular, the basal membrane Type IV collagen col4-1, expressed by both neoblasts and muscle cells, is needed for proper planarian tissue maintenance and regeneration, as well as to restrict neoblast number and promote progenitor progression and cell differentiation. These effects are in part mediated by the EGF signaling pathway, suggesting a role of these ECM components in the control of cell fate specification and symmetric versus asymmetric cell division, as mentioned below [77].…”

“…More recent studies have also revealed the importance of some ECM components such as the EGF repeat-containing genes megf6 and hemicentin to maintain the structure of the basal lamina, restrict the stem cell compartment and retain the parenchymal cell localization of neoblasts and differentiated cells [71,72]. Although some ECM genes are expressed in other tissue types, including intestine, parenchymal cells, neoblasts, neurons and pigment cells, among others [77], muscle cells are the main source of ECM and express core components such as collagen genes [71,77]. Interestingly, these basal membrane collagen and fibrillar collagen genes have been recently shown to play differential roles regulating proliferation during neoblast repopulation, as well as controlling lineage progression.…”

“…Interestingly, recent studies have started to identify some of the molecular mechanisms that control the balance of symmetric versus asymmetric cell division of neoblasts. The interaction between the ECM component type IV collagen, the discoidin domain receptor (DDR) and the EGF ligand Neuregulin-7 (NRG-7), via the NRG-7/EGFR pathway, have been found to be important in the process [77]. On the one hand, supporting neurons interact with COL-IV from the extracellular matrix via the DDR1 receptor and regulate the expression of nrg-7 in neurons [77].…”