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Journal Article Ppublish 8 citations

PubMed: 38367864 DOI: 10.1016/j.jconrel.2024.02.019

Differentiated mesenchymal stem cells-derived exosomes immobilized in decellularized sciatic nerve hydrogels for peripheral nerve repair.

J Control Release 368:24-41

Authors: Bo Liu, Olawale A Alimi, Yanfei Wang, Yunfan Kong, Mitchell Kuss, Mena Asha Krishnan, Guoku Hu, Yi Xiao, Jixin Dong, Dominick J DiMaio, Bin Duan

Affiliations

  • Mary & Dick Holland Regenerative Medicine Program and Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Mary & Dick Holland Regenerative Medicine Program and Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Erie, PA 16509, USA.
  • Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Mary & Dick Holland Regenerative Medicine Program and Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Division of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Mechanical and Materials Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.

Abstract

Peripheral nerve injury (PNI) and the limitations of current treatments often result in incomplete sensory and motor function recovery, which significantly impact the patient's quality of life. While exosomes (Exo) derived from stem cells and Schwann cells have shown promise on promoting PNI repair following systemic administration or intraneural injection, achieving effective local and sustained Exo delivery holds promise to treat local PNI and remains challenging. In this study, we developed Exo-loaded decellularized porcine nerve hydrogels (DNH) for PNI repair. We successfully isolated Exo from differentiated human adipose-derived mesenchymal stem cells (hADMSC) with a Schwann cell-like phenotype (denoted as dExo). These dExo were further combined with polyethylenimine (PEI), and DNH to create polyplex hydrogels (dExo-loaded pDNH). At a PEI content of 0.1%, pDNH showed cytocompatibility for hADMSCs and supported neurite outgrowth of dorsal root ganglions. The sustained release of dExos from dExo-loaded pDNH persisted for at least 21 days both in vitro and in vivo. When applied around injured nerves in a mouse sciatic nerve crush injury model, the dExo-loaded pDNH group significantly improved sensory and motor function recovery and enhanced remyelination compared to dExo and pDNH only groups, highlighting the synergistic regenerative effects. Interestingly, we observed a negative correlation between the number of colony-stimulating factor-1 receptor (CSF-1R) positive cells and the extent of PNI regeneration at the 21-day post-surgery stage. Subsequent in vitro experiments demonstrated the potential involvement of the CSF-1/CSF-1R axis in Schwann cells and macrophage interaction, with dExo effectively downregulating CSF-1/CSF-1R signaling.

MeSH

Pharmaceutical Preparations, Microscopy, Electron, Scanning Transmission, Delayed-Action Preparations, Exosomes, Dosage Forms, Colony-Stimulating Factors, Schwann Cells, Peripheral Nerves, Hydrogels, Sciatic Nerve, Macrophage Colony-Stimulating Factor, Mesenchymal Stem Cells, Remyelination

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