Amelioration of ligamentum flavum hypertrophy using umbilical cord mesenchymal stromal cell-derived extracellular vesicles

Cheng Ma; Xin Qi; Yi-Fan Wei; Zhi Li; He-Long Zhang; He Li; Feng-Lei Yu; Ya-Nan Pu; Yong-Can Huang; Yong-Xin Ren

doi:10.1016/j.bioactmat.2022.03.042

Amelioration of ligamentum flavum hypertrophy using umbilical cord mesenchymal stromal cell-derived extracellular vesicles

Bioact Mater. 2022 Apr 8:19:139-154. doi: 10.1016/j.bioactmat.2022.03.042. eCollection 2023 Jan.

Authors

Cheng Ma¹, Xin Qi², Yi-Fan Wei¹, Zhi Li³, He-Long Zhang¹, He Li¹, Feng-Lei Yu¹, Ya-Nan Pu⁴, Yong-Can Huang⁵, Yong-Xin Ren¹

Affiliations

¹ Department of Orthopaedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
² Department of Pathogen Biology and Immunology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
³ Department of Orthopaedics, Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210024, China.
⁴ Outpatient & Emergency Management Department, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
⁵ Shenzhen Engineering Laboratory of Orthopaedic Regenerative Technologies, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, China.

Abstract

Ligamentum flavum (LF) hypertrophy (LFH) has been recognised as one of the key contributors to lumbar spinal stenosis. Currently, no effective methods are available to ameliorate this hypertrophy. In this study, human umbilical cord mesenchymal stromal cell-derived extracellular vesicles (hUCMSC-EVs) were introduced for the first time as promising vehicles for drug delivery to treat LFH. The downregulation of miR-146a-5p and miR-221-3p expressions in human LF tissues negatively correlated with increased LF thickness. The hUCMSC-EVs enriched with these two miRNAs significantly suppressed LFH in vivo and notably ameliorated the progression of transforming growth factor β1(TGF-β1)-induced fibrosis in vitro after delivering these two miRNAs to mouse LF cells. The results further demonstrated that miR-146a-5p and miR-221-3p directly bonded to the 3'-UTR regions of SMAD4 mRNA, thereby inhibiting the TGF-β/SMAD4 signalling pathway. Therefore, this translational study determined the effectiveness of a hUCMSC-EVs-based approach for the treatment of LFH and revealed the critical target of miR-146a-5p and miR-221-3p. Our findings provide new insights into promising therapeutics using a hUCMSC-EVs-based delivery system for patients with lumbar spinal stenosis.

Keywords: ECM, extracellular matrix; Extracellular vesicle; Fibrosis; LF, Ligamentum flavum; LFH, Ligamentum flavum hypertrophy; LSS, Lumbar spinal stenosis; Ligamentum flavum hypertrophy; MRI, magnetic resonance imaging; SMAD, mothers against the decapentaplegic homolog; TGF-β1, transforming growth factor-β1; Umbilical cord mesenchymal stromal cells; hUCMSC-EVs, human umbilical cord mesenchymal stromal cell-derived extracellular vesicles; miR-146a-5p; miR-221-3p.