Infusion of hESC derived Immunity-and-matrix regulatory cells improves cognitive ability in early-stage AD mice

Abstract

Objectives: In this study, we administered immunity-and-matrix regulatory cells (IMRCs) via tail vein (IV) and intracerebroventricular (ICV) injection to 3-month-old 5×FAD transgenic mice to assess the effects of IMRC transplantation on the behaviour and pathology of early-stage Alzheimer's disease (AD). Materials and methods: Clinical-grade human embryonic stem cell (hESC)-derived IMRCs were produced under good manufacturing practice (GMP) conditions. Three-month-old 5×FAD mice were administered IMRCs via IV and ICV injection. After 3 months, the mice were subjected to behavioural tests and electrophysiological analysis to evaluate their cognitive function, memory ability and synaptic plasticity. The effect of IMRCs on amyloid-beta (Aβ)-related pathology was detected by thioflavin-S staining and Western blot. Quantitative real-time PCR, ELISA and immunostaining were used to confirm that IMRCs inhibit neuroinflammation. RNA-seq analysis was performed to measure changes in gene expression and perform a pathway analysis in response to IMRC treatment. Results: IMRC administration via tail vein injection significantly ameliorated cognitive deficits in early-stage AD (5×FAD) mice. However, no significant change was observed in the characteristic pathology of AD in the ICV group. Plaque analysis revealed that IMRCs did not influence either plaque deposition or BACE1 expression. In addition, IMRCs inhibited inflammatory responses and reduced microglial activation in vivo. Conclusions: We have shown that peripheral administration of IMRCs can ameliorate AD pathology and associated cognitive deficits.