Dimeric Thymosin β4 Loaded Nanofibrous Interface Enhanced Regeneration of Muscular Artery in Aging Body through Modulating Perivascular Adipose Stem Cell–Macrophage Interaction

Abstract

Regenerating nonthrombotic and compliant artery, especially in the aging body, remains a major surgical challenge, mainly owing to the inadequate knowledge of the major cell sources contributing to arterial regeneration and insufficient bioactivity of delivered peptides in grafts. Ultrathin nanofibrous sheaths stented with biodegrading elastomer present opening channels and reduced material residue, enabling fast cell recruitment and host remodeling, while incorporating peptides offering developmental cues are challenging. In this study, a recombinant human thymosin β4 dimer (DTβ4) that contains two complete Tβ4 molecules is produced. The adult perivascular adipose is found as the dominant source of vascular progenitors which, when stimulated by the DTβ4‐loaded nanofibrous sheath, enables 100% patency rates, near‐complete structural as well as adequate functional regeneration of artery, and effectively ameliorates aging‐induced defective regeneration. As compared with Tβ4, DTβ4 exhibits durable regenerative activity including recruiting more progenitors for endothelial cells and smooth muscle cells, when incorporated into the ultrathin polycaprolactone sheath. Moreover, the DTβ4‐loaded interface promotes smooth muscle cells differentiation, mainly through promoting M2 macrophage polarization and chemokines. Incorporating artificial DTβ4 into ultrathin sheaths of fast degrading vascular grafts creates an effective interface for sufficient muscular remodeling thus offering a robust tool for vessel replacement.

Pharmacological manipulation of macrophage autophagy effectively rejuvenates the regenerative potential of biodegrading vascular graft in aging body

“…The vascular grafts were composed of PGS core and PCL/collagen nanofibrous sheath as described previously [ 5 ]. In brief, the sodium citrate tubes and the NaCl tubes were instilled with PGS respectively and crosslinked at 150 °C for 24 h to obtain two different PGS cores.…”

“…For example, PDGF-BB secreted by anti-inflammatory macrophages can promote the myogenic differentiation of vascular progenitor cells. The crosstalk between macrophages and stem cells plays key role in myogenesis of vascular graft [ 5 ]. The general strategy promoting vascular regeneration involves targeting vascular precursor cells, enhancing endothelialization, and fabricating bioactive biomaterials [ 6 ].…”

“…It has been revealed that inflammation accompanied with aging greatly influenced tissue repair [ 11 , 12 ]. For PGS-PCL composite grafts, both acute inflammations initiated by fast degrading PGS and chronic inflammations caused by slow degrading PCL cannot be resolved by senescent homeostatic mechanisms and may even worsen with aging, which eventually results in adverse vascular remodeling [ 5 ]. The rational design of biodegradable vascular grafts in aging body remains to be investigated.…”

“…Our previous study revealed an interesting phenomenon that autophagy of the recruited macrophages in graft was significantly activated by the immunoregulatory peptides [ 5 ]. Autophagy is fundamental to eukaryotic cell homeostasis [ 13 ] and is a critical cyto-adaptive response to environmental stresses including starvation, ischemia, hypoxia and infection [ 14 , 15 ].…”

Challenges and strategies for in situ endothelialization and long-term lumen patency of vascular grafts

“…Macrophages, as the key cells in innate immunity, can release multiple molecules modulating in situ endothelialization process [ 277 , 278 ]. It has been reported that TNF-α secreted by macrophages plays a role in regulating migration and differentiation of EPCs and graft development.…”