Article

Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors.

Wyss Institute, Harvard University, Cambridge, MA 02138, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 12/2009; 107(8):3287-92. DOI: 10.1073/pnas.0903875106
Source: PubMed

ABSTRACT Regenerative efforts typically focus on the delivery of single factors, but it is likely that multiple factors regulating distinct aspects of the regenerative process (e.g., vascularization and stem cell activation) can be used in parallel to affect regeneration of functional tissues. This possibility was addressed in the context of ischemic muscle injury, which typically leads to necrosis and loss of tissue and function. The role of sustained delivery, via injectable gel, of a combination of VEGF to promote angiogenesis and insulin-like growth factor-1 (IGF1) to directly promote muscle regeneration and the return of muscle function in ischemic rodent hindlimbs was investigated. Sustained VEGF delivery alone led to neoangiogenesis in ischemic limbs, with complete return of tissue perfusion to normal levels by 3 weeks, as well as protection from hypoxia and tissue necrosis, leading to an improvement in muscle contractility. Sustained IGF1 delivery alone was found to enhance muscle fiber regeneration and protected cells from apoptosis. However, the combined delivery of VEGF and IGF1 led to parallel angiogenesis, reinnervation, and myogenesis; as satellite cell activation and proliferation was stimulated, cells were protected from apoptosis, the inflammatory response was muted, and highly functional muscle tissue was formed. In contrast, bolus delivery of factors did not have any benefit in terms of neoangiogenesis and perfusion and had minimal effect on muscle regeneration. These results support the utility of simultaneously targeting distinct aspects of the regenerative process.

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    • "Today, the main challenge to overcome, when designing angiogenic therapies based on recombinant GFs, is the control of their local delivery. Moreover, since angiogenesis involves multiple sequential signals, the delivery of multiple GFs may be required to efficiently promote angiogenesis (Borselli et al., 2010; Anderson et al., 2014). For example, systems engineered to reproduce the sequential presentation of the factors controlling the phases of endothelial morphogenesis and vessel maturation may promote a more physiological vascularization (Richardson et al., 2001; Hao et al., 2007; Ruvinov et al., 2011; Brudno et al., 2013). "
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    Frontiers in Bioengineering and Biotechnology 04/2015; 3(45). DOI:10.3389/fbioe.2015.00045
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    • ". The little fibrosis demonstrated by ischemic limbs treated with PRGF is consistent with previous results obtained with the application of PRGF in damaged tendons which exhibited an absence of scarring [39], or more recently in ocular surface cells exposed to TGF-β1 [45]. IGF-1, VEGF, and HGF are among the GF within PRGF that have been suggested as playing an important role in preventing tissue fibrosis when applied in a sustained and combined manner [11]. Although the TGF-β family drives fibrogenesis, collagen synthesis and deposition, the concurrent presence of TGF-β1, VEGF, IGF-1 and HGF within PRGF may render this therapeutic system in an anti-fibrotic product. "
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    ABSTRACT: PRGF is a platelet concentrate within a plasma suspension that forms an in situ-generated fibrin-matrix delivery system, releasing multiple growth factors and other bioactive molecules that play key roles in tissue regeneration. This study was aimed at exploring the angiogenic and myogenic effect of PRGF on in vitro endothelial cells (HUVEC) and skeletal myoblasts (hSkMb) as well as on in vivo mouse subcutaneously implanted matrigel and on limb muscles after a severe ischemia. Human PRGF was prepared and characterized. Both proliferative and anti-apoptotic responses to PRGF were assessed in vitro in HUVEC and hSkMb. In vivo murine matrigel plug assay was conducted to determine the angiogenic capacity of PRGF, whereas in vivo ischemic hind limb model was carried out to demonstrate PRGF-driven vascular and myogenic regeneration. Primary HUVEC and hSkMb incubated with PRGF showed a dose dependent proliferative and anti-apoptotic effect and the PRGF matrigel plugs triggered an early and significant sustained angiogenesis compared with the control group. Moreover, mice treated with PRGF intramuscular infiltrations displayed a substantial reperfusion enhancement at day 28 associated with a fibrotic tissue reduction. These findings suggest that PRGF-induced angiogenesis is functionally effective at expanding the perfusion capacity of the new vasculature and attenuating the endogenous tissue fibrosis after a severe-induced skeletal muscle ischemia.
    Journal of Controlled Release 01/2015; · 7.26 Impact Factor
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    • ". The little fibrosis demonstrated by ischemic limbs treated with PRGF is consistent with previous results obtained with the application of PRGF in damaged tendons which exhibited an absence of scarring [39], or more recently in ocular surface cells exposed to TGF-β1 [45]. IGF-1, VEGF, and HGF are among the GF within PRGF that have been suggested as playing an important role in preventing tissue fibrosis when applied in a sustained and combined manner [11]. Although the TGF-β family drives fibrogenesis, collagen synthesis and deposition, the concurrent presence of TGF-β1, VEGF, IGF-1 and HGF within PRGF may render this therapeutic system in an anti-fibrotic product. "
    [Show abstract] [Hide abstract]
    ABSTRACT: PRGF is a platelet concentrate within a plasma suspension that forms an in situ-generated fibrin-matrix delivery system, releasing multiple growth factors and other bioactive molecules that play key roles in tissue regeneration. This study was aimed at exploring the angiogenic and myogenic effect of PRGF on in vitro endothelial cells (HUVEC) and skeletal myoblasts (hSkMb) as well as on in vivo mouse subcutaneously implanted matrigel and on limb muscles after a severe ischemia. Human PRGF was prepared and characterized. Both proliferative and anti-apoptotic responses to PRGF were assessed in vitro in HUVEC and hSkMb. In vivo murine matrigel plug assay was conducted to determine the angiogenic capacity of PRGF, whereas in vivo ischemic hind limb model was carried out to demonstrate PRGF-driven vascular and myogenic regeneration. Primary HUVEC and hSkMb incubated with PRGF showed a dose dependent proliferative and anti-apoptotic effect and the PRGF matrigel plugs triggered an early and significant sustained angiogenesis compared with the control group. Moreover, mice treated with PRGF intramuscular infiltrations displayed a substantial reperfusion enhancement at day 28 associated with a fibrotic tissue reduction. These findings suggest that PRGF-induced angiogenesis is functionally effective at expanding the perfusion capacity of the new vasculature and attenuating the endogenous tissue fibrosis after a severe-induced skeletal muscle ischemia. Copyright © 2015. Published by Elsevier B.V.
    Journal of Controlled Release 01/2015; 202. DOI:10.1016/j.jconrel.2015.01.029 · 7.26 Impact Factor
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