Intracerebroventricular human mesenchymal stem cells induce MMP9-driven transient inflammation in Alzheimer's disease

Mesenchymal stem cells (MSCs) are often considered hypoimmunogenic. However, a transient fever observed after intracerebroventricular (ICV) administration in a clinical trial suggests an acute host response. This study examines the mechanisms underlying this reaction, with a focus on MSC migration and the role of matrix metalloproteinase-9 (MMP9).

We analyzed cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients treated with saline (n = 3) or human MSCs (hMSCs) (n = 6) using an exploratory protease array, followed by enzyme-linked immunosorbent assay (ELISA). The function of MMP9 was examined further through in-vitro migration and lipopolysaccharide (LPS) stimulation assays in MMP9-silenced hMSCs (siMMP9-hMSCs). In-vivo, siMMP9-hMSCs were delivered ICV into 5xFAD mice to evaluate cell distribution and immune responses.

CSF protease profiling of AD patients revealed that MSC administration increased MMP9 levels. MMP9 knockdown reduced hMSC migration and attenuated LPS induced cytokine increase in the conditioned media (TNF-α and IL-1β) or in the hMSC lysates (IL-1β, IL-6, and CRP) in-vitro. In 5xFAD mice, siMMP9-hMSCs exhibited altered migration and inflammation signatures, characterized by restricted periventricular distribution accompanied by increased CD45 leukocyte accumulation and caspase-3 activity. Naïve hMSCs, on the other hand, dispersed more broadly.

MMP9 promotes the migration of hMSCs and influences the initial interactions between the host and the graft after ICV delivery. Loss of MMP9 activity limits dispersion and is associated with increased local immune activation. This highlights the importance of MMP9-dependent processes in the early post-transplantation phase. These findings may inform strategies to optimize the safety of central nervous system-directed stem cell therapies.

ClinicalTrials.gov Identifier: NCT02054208.