Surface Tethering of Stem Cells with Nanostimulators for Enhanced Ischemic Tissue Treatment

Stem cell transplantation has been a promising treatment for peripheral arterial diseases in
the past decade. Stem cells act as living bioreactors of paracrine factors that orchestrate tissue
regeneration. Pre-stimulated adipose-derived stem cells (ADSCs) have been proposed as potential
candidates but have been met with challenges in activating their secretory activities for clinical
use. Here, we propose that tethering ADSC surface with nanoparticles releasing tumor necrosis
factor α (TNFα), named nanostimulator, would stimulate cellular secretory activity in situ. We
examined this hypothesis by complexing octadecylamine-grafted hyaluronic acid onto a liposomal
carrier of TNFα. Hyaluronic acid increased the liposomal stability and association to CD44 on
ADSC surface. ADSCs tethered with these TNFα carriers exhibited up-regulated secretion of proangiogenic
vascular endothelial growth factor and immunomodulatory prosteoglandin E2 (PGE2)
while decreasing secretion of anti-angiogenic pigment epithelium-derived factors. Accordingly,
ADSCs tethered with nanostimulators promoted vascularization in a 3D microvascular chip and
enhanced recovery of perfusion, walking, and muscle mass in a murine ischemic hindlimb
compared to untreated ADSCs. We propose that this surface tethering strategy for in situ
stimulation of stem cells would replace the costly and cumbersome pre-conditioning process and
expedite clinical use of stem cells for improved treatments of various injuries and diseases.