Engineering Cadherin-Guided MSC Aggregates to Empower Synergistic Neurovascular Repair After Stroke

Abstract

Ischemic stroke inflicts severe neurological damage by disrupting the neurovascular unit. While promising, mesenchymal stem cell (MSC) therapies are hampered by poor posttransplantation survival and nonspecific secretomes. Here, we introduce a bioengineering strategy that employs cadherin-functionalized interfaces to generate cohesive multicellular MSC aggregates (Cad-MAs). Priming MSCs with recombinant N-cadherin and VE-cadherin stimulated endogenous cadherin expression and facilitated the self-assembly of stable spheroids with reinforced intercellular adherens junctions. Cad-MAs exhibited increased resistance to inflammatory stress and anoikis, and secreted a reparative profile enriched in neurotrophic and angiogenic factors, as well as exosomes carrying therapeutic miRNAs such as miR-21-5p and miR-126-3p. The in vitro analyses indicate that cadherin-empowered assembly yields MSC aggregates in which structural stability is coupled with a pro-survival, proregenerative phenotype. Furthermore, in a mouse stroke model, systemically delivered Cad-MAs significantly outperformed conventional dissociated MSCs, promoting functional recovery, reducing infarct volume, and improving cerebral perfusion alongside evidence of enhanced angiogenesis and preservation of blood-brain barrier integrity markers. This approach, termed functional aggregation-induced emergence (F-AIE), provides a versatile framework for engineering integrated cellular therapeutics with tailored functional outputs for regenerative applications.

Keywords

ischemic stroke / mesenchymal stem cells / cadherin / cadherin-guided aggregates / cell therapy

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