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.

Keywords: cell therapy; extracorporeal shockwave therapy; focused ultrasound; homing; low-intensity ultrasound; mesenchymal stromal cells; regenerative medicine; ultrasound.

Figure 1

Ultrasound modalities. Schematic of different forms of ultrasound that have been used for enhancing MSC‐based therapies, along with representative waveforms. Intensity values reflect ranges typical of studies in the literature. cFUS, continuous focused ultrasound; cLIUS, continuous low‐intensity ultrasound; HIFU, high‐intensity focused ultrasound; LIPUS, low‐intensity pulsed ultrasound; MSC, mesenchymal stromal cell; pFUS, pulsed focused ultrasound; pHIFU, pulsed high‐intensity focused ultrasound

Figure 2

Ultrasound parameters. A, Representations of various parameters related to pulsed ultrasound, with waveforms represented over space (left) or time (right). B, Representations of the various measures of intensity in pulsed ultrasound. Left, the spatial intensity of a beam of ultrasound over its cross‐sectional area, showing the spatial average and peak. Right, the temporal intensity of several pulses of ultrasound, showing the temporal average and peak, and pulse average

Figure 3

Molecular mechanisms of ultrasound. A, Currently known mechanisms by which pulsed focused ultrasound (pFUS) enhances mesenchymal stromal cell (MSC) homing in vivo. B, The effect of low‐intensity pulsed ultrasound (LIPUS) and extracorporeal shockwave therapy (ESWT) on MSC proliferation and differentiation in vitro. Upregulated markers are listed underneath each lineage. Involved signaling pathways are shown along the arrows