Effect of methacrylic acid beads on the sonic hedgehog signaling pathway and macrophage polarization in a subcutaneous injection mouse model.
Poly(methacrylic acid-co-methyl methacrylate) (MAA) beads promote a vascular regenerative response when used in diabetic wound healing. Previous studies reported that MAA beads modulated the expression of sonic hedgehog (Shh) and inflammation related genes in diabetic wounds. The aim of this work was to follow up on these observations in a subcutaneous injection model to study the host response in the absence of the confounding factors of diabetic wound healing. In this model, MAA beads improved vascularization in healthy mice of both sexes compared to control poly(methyl methacrylate) (MM) beads, with a stronger effect seen in males than females. MAA-induced vessels were perfusable, as evidenced from the CLARITY-processed images. In Shh-Cre-eGFP/Ptch1-LacZ non-diabetic transgenic mice, the increased vessel formation was accompanied by a higher density of cells expressing GFP (Shh) and β-Gal (patched 1, Ptch1) suggesting MAA enhanced the activation of the Shh pathway. Ptch1 is the Shh receptor and a target of the pathway. MAA beads also modulated the inflammatory cell infiltrate in CD1 mice: more neutrophils and more macrophages were noted with MAA relative to MM beads at days 1 and 7, respectively. In addition, MAA beads biased macrophages towards a MHCII-CD206+ ("M2") polarization state. This study suggests that the Shh pathway and an altered inflammatory response are two elements of the complex mechanism whereby MAA-based biomaterials effect vascular regeneration.
Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Suite 407, Toronto, Ontario, Canada M5S 3G9.
Alexandra
A
Lisovsky
Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Suite 407, Toronto, Ontario, Canada M5S 3G9.
David K Y
DK
Zhang
Institute of Biomaterials and Biomedical Engineering, University of Toronto, 164 College Street, Suite 407, Toronto, Ontario, Canada M5S 3G9; Department of Chemical Engineering and Applied Chemistry, University of Toronto, 164 College Street, Suite 407, Toronto, Ontario, Canada M5S 3G9. Electronic address: michael.sefton@utoronto.ca.
Michael V
MV
Sefton
D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000254:growth & development; D002452:Cell Count; D016764:Cell Polarity / Q000187:drug effects*; D005260:Female; D049452:Green Fluorescent Proteins / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D007279:Injections, Subcutaneous; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008689:Methacrylates / Q000494:pharmacology*; D051379:Mice; D008863:Microspheres; D023421:Models, Animal; D015398:Signal Transduction / Q000187:drug effects; D001616:beta-Galactosidase / Q000378:metabolism
D053823:Hedgehog Proteins; D008689:Methacrylates; D049452:Green Fluorescent Proteins; C008384:methacrylic acid; D001616:beta-Galactosidase
Macrophage polarization; Methacrylic acid; Sonic hedgehog