Urokinase-dependent plasminogen activation is required for efficient skeletal muscle regeneration in vivo

Lluı́s, Frederic; Roma, Josep; Suelves, Mònica; Parra, Maribel; Aniorte, Gloria; Gallardo, Eduard; Illa, Isabel; Rodríguez, Laura; Hughes, Simon M.; Carmeliet, Peter; Roig, Manuel G.; Muñoz‐Cánoves, Pura

doi:10.1182/blood.v97.6.1703

Cited by 105 publications

(133 citation statements)

References 33 publications

Supporting

Mentioning

126

Contrasting

Order By: Relevance

“…6G). We hypothesized that injured muscles may transiently generate sufficient prosurvival signals from infiltrating macrophages (46)(47)(48)(49)(50) that act in synergy with the GF-free scaffolds, enhancing MuSC engraftment. Hence, we reasoned that GFs codelivered within aPA scaffolds might improve MuSC engraftment and overcome the need for notexin injury in the standard injection paradigm, allowing for a minimal injury approach more favorable to clinical application (Fig.…”

Section: Biomimetic Scaffolds Loaded With Gfs Enhance Engraftment Ofmentioning

confidence: 99%

Injectable biomimetic liquid crystalline scaffolds enhance muscle stem cell transplantation

Sleep

Cosgrove

McClendon

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Muscle stem cells are a potent cell population dedicated to efficacious skeletal muscle regeneration, but their therapeutic utility is currently limited by mode of delivery. We developed a cell delivery strategy based on a supramolecular liquid crystal formed by peptide amphiphiles (PAs) that encapsulates cells and growth factors within a muscle-like unidirectionally ordered environment of nanofibers. The stiffness of the PA scaffolds, dependent on amino acid sequence, was found to determine the macroscopic degree of cell alignment templated by the nanofibers in vitro. Furthermore, these PA scaffolds support myogenic progenitor cell survival and proliferation and they can be optimized to induce cell differentiation and maturation. We engineered an in vivo delivery system to assemble scaffolds by injection of a PA solution that enabled coalignment of scaffold nanofibers with endogenous myofibers. These scaffolds locally retained growth factors, displayed degradation rates matching the time course of muscle tissue regeneration, and markedly enhanced the engraftment of muscle stem cells in injured and noninjured muscles in mice.biomaterials | scaffold | muscle stem cell | cell delivery | muscle regeneration

show abstract

Section: Biomimetic Scaffolds Loaded With Gfs Enhance Engraftment Ofmentioning

confidence: 99%

Injectable biomimetic liquid crystalline scaffolds enhance muscle stem cell transplantation

Sleep

Cosgrove

McClendon

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…However, wound healing studies showed that disturbed plasminogen activation, as observed in plasminogen and uPA-deficient mice, compromised wound healing. 22,23 Expression analysis of uPA in the fracture callus are available, but the involvement of mesenchymal progenitors and their regulation of plasminogen activators is still an enigma. 29,30 The signaling pathway involved in the expression of plasminogen activators and the respective inhibitors has been extensively studied.…”

mentioning

confidence: 99%

“…21 The balance between plasminogen activators and PAI-1 is therefore crucial in the cellular plasminogen activation capacity. 22,23 In addition to the impact on fibrinolysis, the plasminogen activator system is involved in the activation of matrix metalloproteinases (MMP) [24][25][26] and latent growth factors. 27 During development, uPA and tPA deficiency causes an increase in bone mass, which may not be associated with bone healing.…”

mentioning

confidence: 99%

Activated platelets increase fibrinolysis of mesenchymal progenitor cells

Agis

Kandler

Fischer

et al. 2008

Journal Orthopaedic Research

View full text Add to dashboard Cite

Bone regeneration is initiated by the formation of a blood clot. Activated platelets within this fibrin-rich matrix release signaling molecules that can attract mesenchymal progenitor cells. To gain insight into the cellular mechanism by which activated platelets can support the immigration of mesenchymal progenitors, we have tested the hypothesis that platelet-released signaling molecules increase the capacity of bone marrow stromal cells (BMSC) to activate plasminogen. We report herein that platelet-released supernatants (PRS) elevate total urokinase-type plasminogen activator (uPA) and total plasminogen activator inhibitor-1 (PAI-1) levels in BMSC, as assessed by immunoassay. Quantitative polymerase chain reaction showed an upregulation of uPA, uPA receptor, and PAI-1. Zymography and kinetic analysis based on casein hydrolysis revealed enhanced activity of cell-associated uPA upon exposure of BMSC to PRS. Inhibiting c-Jun Nterminal kinase (JNK) and phosphatidylinositol 3-kinase (PI3K) signaling reduced uPA production and decreased plasminogen activation. Corresponding Western blot analysis showed increased phosphorylation of JNK and AKT in BMSC treated with PRS. These results suggest that activated platelets can enhance the plasminogen activation capacity of mesenchymal progenitors through the stimulation of uPA production, requiring JNK and PI3K/AKT signaling. By this mechanism platelets may contribute to the organization of the blood clot during bone regeneration. ß

show abstract

“…Other molecular systems involved in cell migration are required for a proper regeneration because they regulate monocyte/MP entry into damaged muscle (23). Urokinase-type plasminogen activator is required for MP chemotaxis and is necessary for MP migration into skeletal muscle to ensure an efficient regeneration (27). Altogether, these studies demonstrate that MPs are indispensable for efficient muscle regeneration.…”

mentioning

confidence: 69%

Myeloid HIFs Are Dispensable for Resolution of Inflammation during Skeletal Muscle Regeneration

Gondin

Théret

Duhamel

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

International audienceBesides their role in cellular responses to hypoxia, hypoxia-inducible factors (HIFs) are involved in innate immunity and also have anti-inflammatory (M2) functions, such as resolution of inflammation preceding healing. Whereas the first steps of the inflammatory response are associated with proinflammatory (M1) macrophages (MPs), resolution of inflammation is associated with anti-inflammatory MPs exhibiting an M2 phenotype. This M1 to M2 sequence is observed during postinjury muscle regeneration, which provides an excellent paradigm to study the resolution of sterile inflammation. In this study, using in vitro and in vivo approaches in murine models, we demonstrated that deletion of hif1a or hif2a in MPs has no impact on the acquisition of an M2 phenotype. Furthermore, using a multiscale methodological approach, we showed that muscles did not require macrophagic hif1a or hif2a to regenerate. These results indicate that macrophagic HIFs do not play a crucial role during skeletal muscle regeneration induced by sterile tissue damage

show abstract

Urokinase-dependent plasminogen activation is required for efficient skeletal muscle regeneration in vivo

Cited by 105 publications

References 33 publications

Injectable biomimetic liquid crystalline scaffolds enhance muscle stem cell transplantation

Injectable biomimetic liquid crystalline scaffolds enhance muscle stem cell transplantation

Activated platelets increase fibrinolysis of mesenchymal progenitor cells

Myeloid HIFs Are Dispensable for Resolution of Inflammation during Skeletal Muscle Regeneration

Contact Info

Product

Resources

About