Concise Review: Skeletal Muscle as a Delivery Route for Mesenchymal Stromal Cells

Abstract

Mesenchymal stromal cells (MSCs) have demonstrated extensive capacity to modulate a catabolic microenvironment toward tissue repair. The fate, biodistribution, and dwell time of the in vivo delivered MSCs largely depend on the choice of the cell delivery route. Intramuscular (IM) delivery of MSCs is clinically safe and has been used for the effective treatment of local pathologies. Recent findings have shown that the secretome of the IM‐delivered MSCs enters the circulation and provides systemic effects on distant organs. In addition, muscle tissue provides a safe residence for the delivered MSCs and an extended secretorily active dwell time compared with other delivery routes. There are, however, controversies concerning the fate of MSCs post IM‐delivery and, specifically, into an injured site with proinflammatory cues. This review seeks to provide a brief overview of the fate and efficacy of IM‐delivered MSCs and to identify the gaps that require further assessment for adoption of this promising route in the treatment of systemic disease. stem cells translational medicine 2019;8:456–465

Efficacy and safety of mesenchymal stem cells co-infusion in allogeneic hematopoietic stem cell transplantation: a systematic review and meta-analysis

“…However, this dose-response effect may not be beneficial when the MSC dose is above a certain threshold [ 60 , 61 ]. Numerous routes of MSC delivery to the human body have been used, including intramuscular or direct injection into tissues or organs [ 62 , 63 ], intravenous (IV) infusion [ 63 – 65 ], intraarterial (IA) infusion [ 63 , 66 ], and intra-bone marrow injection [ 67 , 68 ]. Topical application of MSCs has been widely used in burn medicine and wound care [ 63 ].…”

Mesenchymal Stromal Cell Therapeutic Delivery: Translational Challenges to Clinical Application

“…Classically, localized topical application or injection of a cell therapy into a specific site or target tissue, e.g., intramuscular or penumbral area of an injury, has been shown to be very useful for precision delivery of MSCs and to increase the engraftment of therapeutic cells at a specific site of interest (14, 27). These strategies are often associated with a tissue replacement strategy or direct paracrine support as a MoA and can be particularly useful when combined with specifically tailored exogenous support systems and biomaterials to guide MSC-host interaction and encourage endogenous therapeutic actions (28, 29).…”

“…In the study by Braid et al IM delivery of MSCs in a mouse model led to survival of human MSCs for up to 5 months after injection. In addition to extended dwell time, IM skeletal muscle fibers provide a highly vascular conduit for local and systemic release of trophic factors and support for MSC paracrine actions (27).…”

Perinatal Cells: A Promising COVID-19 Therapy?

“…The IM route holds great advantages over other administration routes, such as the possibility to administer a higher number of cells and thus potentially increase efficacy (Braid et al, 2018 ; Caplan et al, 2019 ), and the vascularized muscle support provides a channel for systemic release of paracrine mediators. In addition, the large muscle tissue allows for multiple injection sites (Caplan et al, 2019 ; Hamidian Jahromi and Davies, 2019 ). IM delivery has been shown to be safe (reviewed in Caplan et al, 2019 ; Hamidian Jahromi and Davies, 2019 ) in several clinical studies (Winkler et al, 2018 ; Norgren et al, 2019 ) with placenta-derived mesenchymal-like cells [PLacental eXpanded (PLX)-PAD] and is now being tested in a double-blind, multicenter study to evaluate the efficacy of PLX-PAD for the treatment of COVID-19 (NCT04389450).…”

“…In addition, the large muscle tissue allows for multiple injection sites (Caplan et al, 2019 ; Hamidian Jahromi and Davies, 2019 ). IM delivery has been shown to be safe (reviewed in Caplan et al, 2019 ; Hamidian Jahromi and Davies, 2019 ) in several clinical studies (Winkler et al, 2018 ; Norgren et al, 2019 ) with placenta-derived mesenchymal-like cells [PLacental eXpanded (PLX)-PAD] and is now being tested in a double-blind, multicenter study to evaluate the efficacy of PLX-PAD for the treatment of COVID-19 (NCT04389450). PLX-PAD cells are adherent stromal cells isolated from the placenta of healthy women following a cesarean section.…”