Surface Tethering of Inflammation-Modulatory Nanostimulators to Stem Cells for Ischemic Muscle Repair

Abstract

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. Prestimulated 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 the 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 antiangiogenic 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 preconditioning process and expedite clinical use of stem cells for improved treatments of various injuries and diseases.

Hydrogel Loaded with VEGF/TFEB‐Engineered Extracellular Vesicles for Rescuing Critical Limb Ischemia by a Dual‐Pathway Activation Strategy

“…The fluorescent signal was assessed using a CLSM (Leica Microsystems GmbH, Mannheim, Germany). [ 66 ]…”

“…The fluorescent signal was assessed using a CLSM (Leica Microsystems GmbH, Mannheim, Germany). [66] Statistical Analysis: Statistical analyses were carried out using Graph-Pad Prism 7 software (GraphPad Software Inc., USA). All values and error bars were present as mean ± standard deviation.…”

Osteon-mimetic 3D nanofibrous scaffold enhances stem cell proliferation and osteogenic differentiation for bone regeneration

“…These vessels were believed to be related to the paracrine effects of the rADSCs. ADSCs have been found to secrete proangiogenic factors such as vascular endothelial growth factor and monocyte chemoattractant protein-1, 58 thus accelerating angiogenesis around the ossification centers in the ADSC@BLM group.…”

Mechanobiological Strategies to Enhance Stem Cell Functionality for Regenerative Medicine and Tissue Engineering

“…The same group also leveraged PLGA-HA nanoparticles encapsulating antioxidative cargos (epigallocatechin gallate, EGCG) and manganese oxide (MnO 2 ) nanocatalysts) to improve the survival of MSCs in the oxidative tissue microenvironment, which conferred better metabolic and angiogenic potential on the cells ( Teo et al, 2020 ). Similarly, to impact the secretory profile of ADSCs, octadecylamine-grafted HA was complexed onto a liposomal carrier of TNFα, which upregulated the secretion of proangiogenic VEGF and immunomodulatory prostaglandin E2 (PGE2) while decreasing the secretion of antiangiogenic pigment epithelium-derived factors ( Leong et al, 2020 ). TNF-α-tethered ADSCs also promoted vascularization on a chip in vitro as well as perfusion in a murine ischemic hindlimb model in vivo .…”