Pretreatment of UC-MSCs with IFN-α2 improves treatment of liver fibrosis by recruiting neutrophils

  • J Transl Med. 2023 Nov 18;21(1):832. doi: 10.1186/s12967-023-04732-0.
Ye Xie  1 ,  Jia Yao  2 ,  Mengchao Yan  1 ,  Yan Lin  1 ,  Jiayun Wei  1 ,  Haiping Wang  2 ,  Yongcui Mao  1 ,  Pinyan Liu  1 ,  Xun Li  3  4  5
Affiliations
  • 1. The First Clinical Medical College, Lanzhou University, Lanzhou, China.
  • 2. Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China.
  • 3. The First Clinical Medical College, Lanzhou University, Lanzhou, China. [email protected].
  • 4. Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China. [email protected].
  • 5. Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China. [email protected].
PMID: 37980535 DOI: 10.1186/s12967-023-04732-0
Abstract

Background: The use of umbilical cord mesenchymal stem cells (UC-MSCs) is a burgeoning method for the treatment of liver cirrhosis. However, the secretory phenotype and regulatory ability of UC-MSCs are easily affected by their microenvironment. Ensuring a specific microenvironment to enhance the UC-MSCs phenotype is a potential strategy for improving their therapeutic efficacy. The aim of this study was to explore therapeutic UC-MSCs phenotypes for improving liver fibrosis.

Methods: RNA-sequencing was used to analyze the response pattern of UC-MSCs after exposure to the serum of cirrhotic patients with HBV. Using immunohistochemistry, quantitative polymerase chain reaction, and immunofluorescence techniques, we evaluated the therapeutic effect of UC-MSCs pretreated with interferon alpha 2 (IFN-α2) (pre-MSCs) in an animal model of cirrhosis. Immunoblotting, ELISA, and Other techniques were used to analyze the signaling pathways underlying the IFN-induced changes in UC-MSCs.

Results: UC-MSCs exposed to the serum of patients with hepatitis B-induced cirrhosis showed an enhanced response to type I IFN. The activated type I IFN signal induced the highest secretion of colony-stimulating factor 3 (CSF-3), interleukin (IL)-8, and chemokine (C-C motif) ligand 20 (CCL20) by the UC-MSCs. Pre-MSCs showed a higher therapeutic efficacy than untreated UC-MSCs in an animal model of liver fibrosis. Immunohistochemical analysis revealed that pre-MSCs could recruit neutrophils resulting in an increase in the secretion of matrix metalloprotease 8 that alleviated fibrosis. When neutrophils in Animals were depleted, the therapeutic effect of pre-MSCs on fibrosis was inhibited. IFN-α2 altered the secretory phenotype of UC-MSCs by activating phosphorylated signal transducer and activator of transcription 1 and 2 (p-STAT1 and p-STAT2).

Conclusions: Pre-MSCs exhibited enhanced secretion of CSF-3, IL-8, and CCL20 and recruited neutrophils to alleviate fibrosis. This new strategy can improve cell therapy for liver cirrhosis.

Keywords
Cirrhosis; Microenvironment-induced phenotype; Neutrophils; Umbilical cord mesenchymal stem cells.
Products