Metabolic Reprogramming of Neural Stem Cells by Chiral Nanofiber for Spinal Cord Injury

Overview

Journal ACS Nano

Publisher American Chemical Society

Date 2025 Jan 22

PMID 39841801

Authors

Haining Wu

Chao Xing

Beibei Yu

LingLi Guo

Xiaoqiu Dou

Laiben Gao

Shijie Yang

Yongfeng Zhang

Xue Gao

Shengyou Li

Bing Xia

Teng Ma

Yiming Hao

Yujie Yang

Xueli Gao

Yitao Wei

Borui Xue

Qing Zhang

Chuan-Liang Feng

Jinghui Huang

Affiliations

Soon will be listed here.

Abstract

Exogenous neural stem cells (NSCs) have great potential to reconstitute damage spinal neural circuitry. However, regulating the metabolic reprogramming of NSCs for reliable nerve regeneration has been challenging. This report discusses the biomimetic dextral hydrogel (DH) with right-handed nanofibers that specifically reprograms the lipid metabolism of NSCs, promoting their neural differentiation and rapid regeneration of damaged axons. The underlying mechanism is the intrinsic stereoselectivity between DH and fatty acid-binding protein 5 (FABP5), which facilitates the transportation of fatty acids bound to FABP5 into the mitochondria and endoplasmic reticulum, subsequently augmenting fatty acid oxidation (FAO) levels and enriching sphingosine biosynthesis. In the rat SCI model, DH significantly improved the Basso-Beattie-Bresnahan (BBB) locomotor scores (over 3-fold) and the hindlimbs' compound muscle action potential (over 4-fold) compared with the untreated group, conveying a significant return of functional recovery. This finding of nanoscale chirality-dependent NSCs metabolic reprogramming provides insights into understanding stem cell physiology and presents opportunities for regenerative medicine.

References

Tseng T, Tao L, Hsieh F, Wei Y, Chiu I, Hsu S . An Injectable, Self-Healing Hydrogel to Repair the Central Nervous System. Adv Mater. 2015; 27(23):3518-24. DOI: 10.1002/adma.201500762. View

Kawai M, Imaizumi K, Ishikawa M, Shibata S, Shinozaki M, Shibata T . Long-term selective stimulation of transplanted neural stem/progenitor cells for spinal cord injury improves locomotor function. Cell Rep. 2021; 37(8):110019. DOI: 10.1016/j.celrep.2021.110019. View

Bieberich E . It's a lipid's world: bioactive lipid metabolism and signaling in neural stem cell differentiation. Neurochem Res. 2012; 37(6):1208-29. PMC: 3343224. DOI: 10.1007/s11064-011-0698-5. View

Varadarajan S, Hunyara J, Hamilton N, Kolodkin A, Huberman A . Central nervous system regeneration. Cell. 2022; 185(1):77-94. PMC: 10896592. DOI: 10.1016/j.cell.2021.10.029. View

Liu D, Lu G, Shi B, Ni H, Wang J, Qiu Y . ROS-Scavenging Hydrogels Synergize with Neural Stem Cells to Enhance Spinal Cord Injury Repair via Regulating Microenvironment and Facilitating Nerve Regeneration. Adv Healthc Mater. 2023; 12(18):e2300123. DOI: 10.1002/adhm.202300123. View

Ma D, Zhao Y, Huang L, Xiao Z, Chen B, Shi Y . A novel hydrogel-based treatment for complete transection spinal cord injury repair is driven by microglia/macrophages repopulation. Biomaterials. 2020; 237:119830. DOI: 10.1016/j.biomaterials.2020.119830. View

Guo W, Zhang X, Zhai J, Xue J . The roles and applications of neural stem cells in spinal cord injury repair. Front Bioeng Biotechnol. 2022; 10:966866. PMC: 9465243. DOI: 10.3389/fbioe.2022.966866. View

Yao X, Hu Y, Cao B, Peng R, Ding J . Effects of surface molecular chirality on adhesion and differentiation of stem cells. Biomaterials. 2013; 34(36):9001-9. DOI: 10.1016/j.biomaterials.2013.08.013. View

Baddi S, Dang-I A, Huang T, Xing C, Lin S, Feng C . Chirality-influenced antibacterial activity of methylthiazole- and thiadiazole-based supramolecular biocompatible hydrogels. Acta Biomater. 2022; 141:59-69. DOI: 10.1016/j.actbio.2022.01.033. View

10.

Fawal M, Davy A . Impact of Metabolic Pathways and Epigenetics on Neural Stem Cells. Epigenet Insights. 2019; 11:2516865718820946. PMC: 6311566. DOI: 10.1177/2516865718820946. View

11.

Dou X, Mehwish N, Zhao C, Liu J, Xing C, Feng C . Supramolecular Hydrogels with Tunable Chirality for Promising Biomedical Applications. Acc Chem Res. 2020; 53(4):852-862. DOI: 10.1021/acs.accounts.0c00012. View

12.

Alvarez Z, Kolberg-Edelbrock A, Sasselli I, Ortega J, Qiu R, Syrgiannis Z . Bioactive scaffolds with enhanced supramolecular motion promote recovery from spinal cord injury. Science. 2021; 374(6569):848-856. PMC: 8723833. DOI: 10.1126/science.abh3602. View

13.

Furuhashi M, Hotamisligil G . Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov. 2008; 7(6):489-503. PMC: 2821027. DOI: 10.1038/nrd2589. View

14.

Xia B, Gao X, Qian J, Li S, Yu B, Hao Y . A Novel Superparamagnetic Multifunctional Nerve Scaffold: A Remote Actuation Strategy to Boost In Situ Extracellular Vesicles Production for Enhanced Peripheral Nerve Repair. Adv Mater. 2023; 36(3):e2305374. DOI: 10.1002/adma.202305374. View

15.

Fu L, Li L, Bian Q, Xue B, Jin J, Li J . Cartilage-like protein hydrogels engineered via entanglement. Nature. 2023; 618(7966):740-747. DOI: 10.1038/s41586-023-06037-0. View

16.

Xing P, Zhao Y . Controlling Supramolecular Chirality in Multicomponent Self-Assembled Systems. Acc Chem Res. 2018; 51(9):2324-2334. DOI: 10.1021/acs.accounts.8b00312. View

17.

Wei Y, Jiang S, Si M, Zhang X, Liu J, Wang Z . Chirality Controls Mesenchymal Stem Cell Lineage Diversification through Mechanoresponses. Adv Mater. 2019; 31(16):e1900582. DOI: 10.1002/adma.201900582. View

18.

Willis C, Nicaise A, Peruzzotti-Jametti L, Pluchino S . The neural stem cell secretome and its role in brain repair. Brain Res. 2019; 1729:146615. DOI: 10.1016/j.brainres.2019.146615. View

19.

Qian D, Li L, Rong Y, Liu W, Wang Q, Zhou Z . Blocking Notch signal pathway suppresses the activation of neurotoxic A1 astrocytes after spinal cord injury. Cell Cycle. 2019; 18(21):3010-3029. PMC: 6791691. DOI: 10.1080/15384101.2019.1667189. View

20.

Fan B, Wei Z, Yao X, Shi G, Cheng X, Zhou X . Microenvironment Imbalance of Spinal Cord Injury. Cell Transplant. 2018; 27(6):853-866. PMC: 6050904. DOI: 10.1177/0963689718755778. View