4.7 Article

A supramolecular hydrogel based on the combination of YIGSR and RGD enhances mesenchymal stem cells paracrine function via integrin α2β1 and PI3K/AKT signaling pathway for acute kidney injury therapy

Journal

CHEMICAL ENGINEERING JOURNAL
Volume 436, Issue -, Pages -

Publisher

ELSEVIER SCIENCE SA
DOI: 10.1016/j.cej.2022.135088

Keywords

Peptides; Hydrogel; Integrin; Mesenchymal stem cell; Acute kidney injury

Funding

  1. National Key R&D Program of China [2018YFA0108803, 2021YFC1005302, 2018YFE0126600]
  2. Natural Science Foundation of China [82170686, 81921004, 61971441, 82070741]

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A novel Biotin-(D)FYIGSRGD hydrogel was developed by conjugating YIGSR and RGD peptides, which prolonged the survival of MSCs and enhanced their anti-apoptotic and anti-inflammatory effects on kidney injury.
Mesenchymal stem cell (MSC) transplantation has emerged as a promising strategy for the treatment of acute kidney injury (AKI). However, MSC-based therapies are limited by their low cell retention and reduced survival rates at the site of injury. YIGSR (Tyr-Ile-Gly-Ser-Arg) and RGD (Arg-Gly-Asp) peptides derived from the integral components of the extracellular matrix, laminin, and fibronectin, can provide structural support and a suitable microenvironment for MSCs. As their individual effect is inadequate, we conjugated the YIGSR and RGD peptides to form a novel YIGSRGD peptide. We speculated that the conjugated peptide could be more efficient in promoting the survival and therapeutic efficacy of MSCs than the individual peptides. Moreover, to provide a conducive microenvironment for MSCs, we covalently linked biocompatible biotin to a D-amino acid (F-D), which conferred resistance against enzymatic degradation. This increased the stability of YIGSRGD as a functional scaffold and led to the development of a novel, bioactive and biocompatible Biotin-(D)FYIGSRGD hydrogel. The survival of MSCs was monitored using bioluminescence imaging. The roles of the integrin alpha 2 beta 1 and PI3K/AKT pathway in the secretion of important curative cytokines, such as, HGF, VEGFa, and IL-10 were elucidated by silencing them. Results showed that the Biotin-(D)FYIGSRGD hydrogel prolonged survival and augmented the paracrine function of MSCs, thereby enhancing their anti-apoptotic and anti-inflammatory effects on the damaged kidney. These findings indicate that the proposed hydrogel can enhance the therapeutic effects and applicability of MSCs via the YIGSRGD/integrin alpha 2 beta 1/PI3K/AKT axis to promote kidney repair in AKI.

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