# Human Umbilical Cord Mesenchymal Stem Cells Modulate Cytokine Secretion of CD4+ T Cell in Systemic Lupus Erythematosus by Inhibiting HSP90AA1 in the Glucose‐Activated PI3K‐AKT Pathway

## TL;DR

Human umbilical cord stem cells reduce inflammation in lupus by inhibiting a key protein in a glucose-related pathway in immune cells.

## Contribution

This study reveals that hUC-MSCs treat lupus by suppressing HSP90AA1 in the glucose-driven PI3K-AKT pathway in CD4+ T cells.

## Key findings

- hUC-MSCs reduced glucose metabolism and pro-inflammatory cytokines in SLE CD4+ T cells.
- Inhibition of HSP90AA1 in the PI3K-AKT pathway was linked to the anti-inflammatory effects of hUC-MSCs.
- Animal experiments confirmed reduced glucose metabolism and inflammation with hUC-MSC treatment.

## Abstract

Treatment with human umbilical cord mesenchymal stem cells (hUC‐MSCs) attenuated the clinical manifestations of systemic lupus erythematosus (SLE). We investigated the metabolic mechanism whereby hUC‐MSCs modify CD4+ T cell cytokine secretion in lupus.

The study enrolled 30 untreated lupus patients and 20 sex, age, and body mass index matched healthy controls (HCs). CD4+ T cells were isolated by magnetic sorting, and stimulated with anti‐CD3/CD28. The hUC‐MSCs treatment (MSCT) groups were coculturing hUC‐MSCs to CD4+ T cells from moderate and severe SLE (SLE‐MS) groups for 72 h at ratios of 1:25 (T1), 1:10 (T2), and 1:5 (T3). Cytokine concentration and proliferation of the CD4+ T cells were measured by Luminex liquid chip assay and cell counting kit‐8, respectively. Glucose metabolic capacity was measured by Seahorse real‐time metabolic analysis. The role of hUC‐MSCs on cytokine secretion was analyzed by transcriptome sequencing. Glucose enzymes levels and HSP90AA1/PI3K/AKT pathway activity were analyzed by real‐time quantitative PCR and western blot. The CD4+ T cell subsets were detected by flow cytometry.

Compared with HCs, the enhanced glycolysis and mitochondrial oxygen consumption of SLE‐CD4+ T cells were positively associated with disease activity. Treatment with hUC‐MSCs proportionally decreased glucose metabolism and proliferation of SLE‐CD4+ T cells. The hUC‐MSCs treatment significantly diminished supernatant concentrations of interferon‐γ, tumor necrosis factor‐α, interleukin (IL)‐4, and IL‐17 in SLE‐MS group, as well as inhibited HSP90AA1 in the glucose‐activated PI3K‐AKT pathway. In animal experiment, the systemic administration of hUC‐MSCs and inhibition of HSP90AA1 resulted in a reduction of glucose metabolites, enzymes, pro‐inflammatory factor levels, and HSP90AA1/PI3K/AKT signaling pathway activity.

The hUC‐MSCs treatment inhibited overactive glucose metabolism of SLE‐CD4+ T cells. HSP90AA1 in the PI3K‐AKT pathway induced by the glucose metabolism may be involved in the anti‐inflammatory function of hUC‐MSCs treatment.

CD4+ T cells in SLE exhibit overactive glucose metabolism. Treatment with hUC‐MSCs effectively inhibits pro‐inflammatory milieu to promote disease remission by decreasing the expression of HSP90AA1 in the PI3K‐AKT pathway induced by CD4+ T cell glucose metabolic activation.