Tissue-Resident Mesenchymal Stem/stromal Cells (MSC) Modulate the Angiogenic Processes in Brain Arteriovenous Malformations (bAVM).

BACKGROUND

Mesenchymal stem/stromal cells (MSCs) have been mainly studied in the context of cell-based therapy for a variety of medical conditions, including cerebrovascular diseases. However, the role of tissue-resident MSCs in the pathophysiology of cerebrovascular diseases in general and of brain arteriovenous malformation (bAVM) in particular is currently unknown, and was investigated in this study.

METHODS

Human bAVM tissues were used to identify MSCs in situ (n = 10) and to isolate them ex vivo (n = 3). The paracrine effects of bAVM-MSCs on endothelial cells (ECs) were assessed in an ex vivo model using MSC-derived supernatants (SNs) and the EC line HUVEC. Selected functional assays were validated using a second EC line (HCAEC).

RESULTS

In situ, cells with a MSC-like phenotype (CD90posCD105posCD73pos) were found in 7 out of 10 bAVM tissues analysed. Ex vivo, MSCs were isolated from fresh bAVM samples and were subsequently characterized according to the ISCT® criteria. The bAVM-MSC SNs had no effect on the ECs' migration, but promoted the proliferation of the ECs. The strongest stimulatory effect of the bAVM-MSC SNs was observed regarding the ECs' tubulogenesis. Additionally, the bAVM-MSC SN induced a partial endothelial-to-mesenchymal transition in ECs.

CONCLUSIONS

These findings indicate that bAVMs contain tissue-resident MSCs, which can potentially modulate the biology and functions of the ECs in the bAVM microenvironment. Thus, MSCs may play critical roles in the pathophysiology and the progression of this disease.