Dataset Information

Collagen-derived prolyl-hydroxyproline dipeptide promotes cellular homeostasis and lamellipodia-driven cell motility through active β1-integrin in adult tendon cells

ABSTRACT: Collagen-derived hydroxyproline-containing peptides show a variety of biological properties in cells. However, no comprehensive study has yet explored the functional links between Hyp-containing peptides and cellular behavior. Here, we show that the dipeptide prolyl-hydroxyproline (Pro–Hyp) exhibits the most significant effect of a number of di- and tri-peptides on mouse tendon cells. We have shown that the cellular uptake of Pro-Hyp is a carrier-mediated process. In addition, Pro-Hyp promotes differentiation/maturation of tendon cells with modulation of lineage-specific factors, has profound effects on cellular phenotypes such as cell proliferation with significantly upregulated ERK-phosphorylation and extracellular matrix production with increased type I collagen network organization, and induced significant chemotactic activity in vitro. Proteomics analysis has identified cellular assembly and organizations, and movement as predicted linked-network pathways in response to Pro-Hyp. Mechanistically, cells treated with Pro-Hyp demonstrate increased directional persistence and significantly increased directed motility and migration velocity, which are accompanied by elongated lamellipodial protrusions with increased active β1-integrin-containing focal contacts and reorganizations of thicker peripheral F-actin fibrils. Thus, our findings document the molecular basis of the functional benefits of Pro-Hyp dipeptide in cellular behavior. Such dynamic properties of collagen-derived Pro-Hyp dipeptide could lead the way to its application to translational medicine.

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Tendon

SUBMITTER: Rosalind Jenkins

LAB HEAD: Rosalind E Jenkins

PROVIDER: PXD020374 | Pride | 2022-09-28

REPOSITORIES: Pride

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			Action	DRS
	KIiTRAQ1CEX39-40091219.wiff	Wiff
	KIiTRAQ1CEX39-40091219.wiff.scan	Wiff
	KIiTRAQ1CEX41-42091219.wiff	Wiff
	KIiTRAQ1CEX41-42091219.wiff.scan	Wiff
	KIiTRAQ1CEX43-44091219.wiff	Wiff

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The dipeptide prolyl-hydroxyproline promotes cellular homeostasis and lamellipodia-driven motility via active β1-integrin in adult tendon cells.

Ide Kentaro K Takahashi Sanai S Sakai Keiko K Taga Yuki Y Ueno Tomonori T Dickens David D Jenkins Rosalind R Falciani Francesco F Sasaki Takako T Ooi Kazuhiro K Kawashiri Shuichi S Mizuno Kazunori K Hattori Shunji S Sakai Takao T

The Journal of biological chemistry 20210523 1

Collagen-derived hydroxyproline (Hyp)-containing peptides have a variety of biological effects on cells. These bioactive collagen peptides are locally generated by the degradation of endogenous collagen in response to injury. However, no comprehensive study has yet explored the functional links between Hyp-containing peptides and cellular behavior. Here, we show that the dipeptide prolyl-4-hydroxyproline (Pro-Hyp) exhibits pronounced effects on mouse tendon cells. Pro-Hyp promotes differentiatio ...[more]

PMID: 34029590

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Project description:Adhesion formation after flexor tendon repair remains a clinical problem. Early postoperative motion after tendon repair has been demonstrated to reduce adhesion formation while increasing tendon strength. It is hypothesized that during mobilization, tendon cells experience mechanical shear forces that alter their biology in a fashion that reduces scar formation but also activates key genes involved in tendon healing. To test this hypothesis, primary intrinsic tenocyte cultures were established from flexor tendons of 20 Sprague-Dawley rats and sheared at 50 rpm (0.41 Pa) using a cone viscometer for 6 and 12 hours. Total RNA was harvested and compared with time-matched unsheared controls using cDNA microarrays and Northern blot analysis. Microarray analysis demonstrated that mechanical shear stress induced an overall "antifibrotic" expression pattern with decreased transcription of collagen type I and collagen type III. Shear stress down-regulated profibrotic molecules in the platelet-derived growth factor, insulin-like growth factor, and fibroblast growth factor signaling pathways. In addition, shear stress induced an overall decrease in transforming growth factor (TGF)-beta signaling pathway molecules with down-regulation of TGF-beta2, TGF-beta3, TGF-RI, and TGF-RII expression. Moreover, sheared tendon cells increased expression of matrix metalloproteinases and decreased expression of tissue inhibitors of metalloproteinase, an expression pattern consistent with an antifibrotic increase in extracellular matrix degradation. However, up-regulation of genes implicated in tendon healing, specifically, vascular endothelial growth factor-A and several bone morphogenetic proteins. Interestingly, the known mechanoresponsive gene, TGF-beta1, also implicated in tendon healing, was differentially up-regulated by shear stress. Northern blot validation of our results for TGF-beta1, TGF-beta2, TGF-beta3, and collagen type I demonstrated direct correlation with microarray data.