The role of ultrasound in enhancing mesenchymal stromal cell-based therapies

Abstract

Mesenchymal stromal cells (MSCs) have been a popular platform for cell‐based therapy in regenerative medicine due to their propensity to home to damaged tissue and act as a repository of regenerative molecules that can promote tissue repair and exert immunomodulatory effects. Accordingly, a great deal of research has gone into optimizing MSC homing and increasing their secretion of therapeutic molecules. A variety of methods have been used to these ends, but one emerging technique gaining significant interest is the use of ultrasound. Sound waves exert mechanical pressure on cells, activating mechano‐transduction pathways and altering gene expression. Ultrasound has been applied both to cultured MSCs to modulate self‐renewal and differentiation, and to tissues‐of‐interest to make them a more attractive target for MSC homing. Here, we review the various applications of ultrasound to MSC‐based therapies, including low‐intensity pulsed ultrasound, pulsed focused ultrasound, and extracorporeal shockwave therapy, as well as the use of adjunctive therapies such as microbubbles. At a molecular level, it seems that ultrasound transiently generates a local gradient of cytokines, growth factors, and adhesion molecules that facilitate MSC homing. However, the molecular mechanisms underlying these methods are far from fully elucidated and may differ depending on the ultrasound parameters. We thus put forth minimal criteria for ultrasound parameter reporting, in order to ensure reproducibility of studies in the field. A deeper understanding of these mechanisms will enhance our ability to optimize this promising therapy to assist MSC‐based approaches in regenerative medicine.

Pulsed focused ultrasound enhances the therapeutic effect of mesenchymal stromal cell-derived extracellular vesicles in acute kidney injury

“…pFUS presents a promising method for optimizing MSC-based therapies [28]. It is a non-invasive procedure that can be precisely targeted to deep structures in the body and has an excellent safety profile [32,34]; indeed, focused ultrasound is already FDA-approved for various clinical applications [41].…”

“…Despite the growing interest in EVs for regenerative applications, there remains an unmet need to improve their therapeutic effect. One promising avenue of optimization could be the use of pulsed focused ultrasound (pFUS) [28]. pFUS uses short-duration, high-intensity pulses of sound waves to non-destructively sonicate target tissues.…”

“…Instead, pFUS was shown to act through protein intermediates to spur endogenous proliferation pathways, an effect which synergized with MSCs. These two mechanisms may not necessarily be at odds with one another, but may instead reflect differences in ultrasound parameters leading to differences in subsequent bioeffects [28]. Although there have been many studies on the effect of pFUS on MSC therapy, little is known about its effect on EV therapy.…”

Ile‐Lys‐Val‐ala‐Val (IKVAV) peptide for neuronal tissue engineering

“…When conjugated to a poly (ethylene glycol) (PEG)-based hydrogel, 10 μM of short IKVAV showed the greatest ability to promote migration than concentrations of 50 and 100 μM. 23…”

A Novel Approach to Deliver Therapeutic Extracellular Vesicles Directly into the Mouse Kidney via Its Arterial Blood Supply

“…Even less studied are methods to further optimize EV homing to specific target tissues. While various surface engineering, genetic, and adjuvant approaches may enhance EV homing [21,32,36], these approaches are often resource-costly; locoregional delivery may be one of the most direct ways to optimize EV therapy. Our IA delivery of EVs restored physiological markers of kidney function (BUN, creatinine), reduced histological and molecular markers of kidney injury (KIM-1, TIMP-1, NGAL, FGF23) [37], attenuated inflammation (TNF-α, IL-6), and spurred cellular proliferation (Ki67, FGF2).…”