Mesenchymal stem cells and extracellular matrix scaffold promote muscle regeneration by synergistically regulating macrophage polarization toward the M2 phenotype

Abstract

BackgroundSkeletal muscle plays an important role in the body’s physiology but there are still no effective treatments for volumetric muscle loss (VML) resulting from severe traumatic injury or tumor excision. Recent studies show that a tissue engineering strategy using a compound containing mesenchymal stem cells (MSCs) and decellularized extracellular matrix (ECM) scaffold generates significant regenerative effects on VML injury, but the underlying mechanisms are not fully understood.MethodsThe characteristics of human umbilical cord MSCs, including multiplication capacity and multidifferentiation ability, were determined. We constructed a compound containing MSCs and decellularized ECM scaffold which was used for tissue regeneration in a VML model.ResultsWe found that MSCs and decellularized ECM scaffold generated synergistic effects on promoting skeletal muscle tissue regeneration. Interestingly, both MSCs and decellularized ECM scaffold could promote macrophage polarization toward the M2 phenotype and suppress macrophage polarization toward the M1 phenotype, which is widely regarded as an important promoting factor in tissue regeneration. More importantly, MSCs and decellularized ECM scaffold generate synergistic promoting effects on macrophage polarization toward the M2 phenotype, not just an additive effect.ConclusionsOur findings uncover a previously unknown mechanism that MSCs and decellularized ECM scaffold promote tissue regeneration via collaboratively regulating macrophage polarization.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-0821-5) contains supplementary material, which is available to authorized users.

Adipose-tissue-derived therapeutic cells in their natural environment as an autologous cell therapy strategy: the microtissue-stromal vascular fraction

“…Successful adipose tissue formation can be observed with decellularised adipose tissue ECM combined with ASCs after 8 weeks in rats (Wang et al, 2013b). The regenerative macrophage-regulating interplay between MSCs and heart-tissue ECM can also be observed after decellularisation and reseeding of ECM scaffold in muscle regeneration (Qiu et al, 2018). In contrast, the gentle isolation procedure described resulted in therapeutic cells without dissociation and denaturation from the surrounding ECM, thereby making the procedure of decellularisation and reseeding redundant and providing a gently treated microtissue, which might positively influence a balanced M1/M2 macrophage response.…”

“…ECM components directly influence cell behaviour, including adhesion, spreading, proliferation and migration (Geutjes et al, 2010;Kim et al, 2012;Prockop, 2007;Wang et al, 2013a), suggesting a positive effect on the cells embedded in the microtissue-SVF. Qiu et al (2018) employ decellularised fat tissue ECM as a scaffold for reseeding MSCs, resulting in improved regenerative efficacy in muscle tissue injury. Beside the typical IFATS-defined SVF-cell surface markers for mesenchymal, endothelial and haematopoietic cells (Bourin et al, 2013), the microtissue-SVF contained a broad range of cell types including pericytic, blood and lymphatic vascular and epithelial cells.…”

Biomaterial and stem cell‐based strategies for skeletal muscle regeneration

“…After 42 days of recovery, the BMMC injected ECM group showed more blood vessels, regenerating skeletal myofibers, and functional recovery than ECM treatment alone. Qui et al repaired VML injured rat hindlimb muscles with human umbilical cord MSCs and decellularized porcine cardiac ECM scaffolds . The treatment groups included decellularized ECM powder, MSC aggregates, or the combination of the two.…”

“…Qui et al repaired VML injured rat hindlimb muscles with human umbilical cord MSCs and decellularized porcine cardiac ECM scaffolds. 149 The treatment groups included decellularized ECM powder, MSC aggregates, or the combination of the two. At 8 weeks post-injury, the compound group showed improved muscle regeneration and functional recovery along with reduced collagen deposition compared to the other treatment groups.…”

The Role of Metabolic Remodeling in Macrophage Polarization and Its Effect on Skeletal Muscle Regeneration

“…Resveratrol pro-M2 activity has been suggested to promote vascularization in tissue engineering applications (292,349,371). Also, transplantation of acellular ECM scaffolds improves performance of diseased muscles by promoting M2 polarization and activating MPCs (274,278); however, other authors showed that, conversely from vital grafts, devitalized grafts were unable to promote an anti-inflammatory phenotype and regeneration in vivo (100).…”