Herpes Simplex Virus Infection Alters the Immunological Properties of Adipose-Tissue-Derived Mesenchymal-Stem Cells

Int J Mol Sci. 2023 Jul 26;24(15):11989. doi: 10.3390/ijms241511989.

Abstract

The proper functioning of mesenchymal stem cells (MSCs) is of paramount importance for the homeostasis of the body. Inflammation and infection can alter the function of MSCs, which can also affect the regenerative potential and immunological status of tissues. It is not known whether human herpes simplex viruses 1 and 2 (HSV1 and HSV2), well-known human pathogens that can cause lifelong infections, can induce changes in MSCs. In non-healing ulcers, HSV infection is known to affect deeper tissue layers. In addition, HSV infection can recur after initially successful cell therapies. Our aim was to study the response of adipose-derived MSCs (ADMSCs) to HSV infection in vitro. After confirming the phenotype and differentiation capacity of the isolated cells, we infected the cells in vitro with HSV1-KOS, HSV1-532 and HSV2 virus strains. Twenty-four hours after infection, we examined the gene expression of the cells via RNA-seq and RT-PCR; detected secreted cytokines via protein array; and determined autophagy via Western blot, transmission electron microscopy (TEM) and fluorescence microscopy. Infection with different HSV strains resulted in different gene-expression patterns. In addition to the activation of pathways characteristic of viral infections, distinct non-immunological pathways (autophagy, tissue regeneration and differentiation) were also activated according to analyses with QIAGEN Ingenuity Pathway Analysis, Kyoto Encyclopedia of Genes and Genome and Genome Ontology Enrichment. Viral infections increased autophagy, as confirmed via TEM image analysis, and also increased levels of the microtubule-associated protein light chain 3 (LC3B) II protein. We identified significantly altered accumulation for 16 cytokines involved in tissue regeneration and inflammation. Our studies demonstrated that HSV infection can alter the viability and immunological status of ADMSCs, which may have implications for ADMSC-based cell therapies. Alterations in autophagy can affect numerous processes in MSCs, including the inhibition of tissue regeneration as well as pathological differentiation.

Keywords: adipose-derived mesenchymal stem cells; gene expression; inflammation.

MeSH terms

  • Cytokines / metabolism
  • Herpes Simplex* / pathology
  • Herpesvirus 1, Human* / physiology
  • Herpesvirus 2, Human
  • Humans
  • Inflammation / metabolism
  • Mesenchymal Stem Cells* / metabolism

Substances

  • Cytokines

Grants and funding

This work was supported by the National Research, Development, and Innovation Office (NKFI PD 132570 to Z.V.) and GINOP PLUSZ-2.1.1-21 project (co-financed by the European Union and the European Regional Development Fund) Z.V. was supported by the Bolyai János Postdoctoral Fellowship (BO/00190/20/5) and the ÚNKP-22-5 Bolyai+ Fellowship (ÚNKP-ÚNKP-22-5-SZTE-319) financed by the New National Excellence Program of the Hungarian Ministry for Innovation and Technology from the source of the National Research Development and Innovation Fund. Project no. TKP2021-EGA-28 and TKP2021-EGA-32 has been implemented with the support provided by the Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund, financed under the TKP2021-EGA funding scheme. L.K. was supported by the New National Excellence Program of the Hungarian Ministry for Innovation and Technology from the source of the National Research Development and Innovation Fund. K.L-HCEMM: H2020-EU.4.a. Klara Megyeri was supported by Interreg V-A Romania-Hungary Programme (Project eMS code: ROHU339). B.G. and Z.B.-C. were supported by the NKFI K 135084 grant.