Abstract:Although growth factors (GFs) are key molecules for regenerative medicine, their use has been limited by issues associated with suboptimal delivery systems and incomplete understanding of their signaling dynamics. Here, we explored how proinflammatory signals affect GF regenerative potential. Using bone regeneration in mouse, we found that the regenerative capacity of two clinically relevant GFs (BMP-2 and PDGF-BB) is impaired by interleukin-1 receptor (IL-1R1). Mechanistically, IL-1R1 activation in bone-formi… Show more
“…The engineered factors displayed a great increase in affinity for the ECM protein tested (Supplementary Fig. 2 , Supplementary Table 1 ) 22 . Fig.…”
Section: Resultsmentioning
confidence: 99%
“…IL-1Ra/PlGF 123–141 and PDGF-BB/PlGF 123–141 were designed to have a 6x histidine tag at their N terminus and the PlGF 123–141 sequence at the C terminus. Recombinant proteins were produced in E. coli BL21 (DE3) via pET-22b (Novagen) as previously decribed 22 . Bacteria were cultured overnight in 10 ml LB medium with 100 μg/ml of ampicillin overnight.…”
Chronic wounds are a major clinical problem where wound closure is prevented by pathologic factors, including immune dysregulation. To design efficient immunotherapies, an understanding of the key molecular pathways by which immunity impairs wound healing is needed. Interleukin-1 (IL-1) plays a central role in regulating the immune response to tissue injury through IL-1 receptor (IL-1R1). Generating a knockout mouse model, we demonstrate that the IL-1–IL-1R1 axis delays wound closure in diabetic conditions. We used a protein engineering approach to deliver IL-1 receptor antagonist (IL-1Ra) in a localised and sustained manner through binding extracellular matrix components. We demonstrate that matrix-binding IL-1Ra improves wound healing in diabetic mice by re-establishing a pro-healing microenvironment characterised by lower levels of pro-inflammatory cells, cytokines and senescent fibroblasts, and higher levels of anti-inflammatory cytokines and growth factors. Engineered IL-1Ra has translational potential for chronic wounds and other inflammatory conditions where IL-1R1 signalling should be dampened.
“…The engineered factors displayed a great increase in affinity for the ECM protein tested (Supplementary Fig. 2 , Supplementary Table 1 ) 22 . Fig.…”
Section: Resultsmentioning
confidence: 99%
“…IL-1Ra/PlGF 123–141 and PDGF-BB/PlGF 123–141 were designed to have a 6x histidine tag at their N terminus and the PlGF 123–141 sequence at the C terminus. Recombinant proteins were produced in E. coli BL21 (DE3) via pET-22b (Novagen) as previously decribed 22 . Bacteria were cultured overnight in 10 ml LB medium with 100 μg/ml of ampicillin overnight.…”
Chronic wounds are a major clinical problem where wound closure is prevented by pathologic factors, including immune dysregulation. To design efficient immunotherapies, an understanding of the key molecular pathways by which immunity impairs wound healing is needed. Interleukin-1 (IL-1) plays a central role in regulating the immune response to tissue injury through IL-1 receptor (IL-1R1). Generating a knockout mouse model, we demonstrate that the IL-1–IL-1R1 axis delays wound closure in diabetic conditions. We used a protein engineering approach to deliver IL-1 receptor antagonist (IL-1Ra) in a localised and sustained manner through binding extracellular matrix components. We demonstrate that matrix-binding IL-1Ra improves wound healing in diabetic mice by re-establishing a pro-healing microenvironment characterised by lower levels of pro-inflammatory cells, cytokines and senescent fibroblasts, and higher levels of anti-inflammatory cytokines and growth factors. Engineered IL-1Ra has translational potential for chronic wounds and other inflammatory conditions where IL-1R1 signalling should be dampened.
“…For example, IL-1R1 signaling has been shown to decrease the responsiveness of MSCs and osteoblasts to growth factors such as bone morphogenetic protein-2 (BMP-2) and platelet-derived growth factor-BB (PDGF-BB). 97 Thus, a sustained co-delivery of BMP-2 and/or PDGF-BB with IL-1 receptor antagonist was shown to increase the regenerative effect of the growth factors in mouse bone regeneration models. 97 …”
Section: Improving the Regenerative Activity Of Endogenous And Transp...mentioning
confidence: 99%
“… 97 Thus, a sustained co-delivery of BMP-2 and/or PDGF-BB with IL-1 receptor antagonist was shown to increase the regenerative effect of the growth factors in mouse bone regeneration models. 97 …”
Section: Improving the Regenerative Activity Of Endogenous And Transp...mentioning
Numerous components of the immune system, including inflammatory mediators, immune cells and cytokines, have a profound modulatory effect on the homeostatic regulation and regenerative activity of endogenous stem cells and progenitor cells. Thus, understanding how the immune system interacts with stem/progenitor cells could build the foundation to design novel and more effective regenerative therapies. Indeed, utilizing and controlling immune system components may be one of the most effective approaches to promote tissue regeneration. In this review, we first summarize the effects of various immune cell types on endogenous stem/progenitor cells, focusing on the tissue healing context. Then, we present interesting regenerative strategies that control or mimic the effect of immune components on stem/progenitor cells, in order to enhance the regenerative capacity of endogenous and transplanted stem cells. We highlight the potential clinical translation of such approaches for multiple tissues and organ systems, as these novel regenerative strategies could considerably improve or eventually substitute stem cell-based therapies. Overall, harnessing the power of the cross-talk between the immune system and stem/progenitor cells holds great potential for the development of novel and effective regenerative therapies.
“…Targeting of the pro-inflammatory cytokine interleukin-1 (IL-1) and its receptor (IL-1R1) is particularly notable in the context of biomaterial-mediated immunomodulation, with inhibition of IL-1R1 signalling shown to enhance the tissue regenerative activity of MSCs [117]. A recent investigation building on this demonstrated the negative impact of IL-1R1 activation on the osteoregenerative capabilities of MSCs [118]. In this study, the inhibition of IL-1 pro-inflammatory signalling through the co-delivery of IL-1 receptor agonist (IL-1Ra) and pro-osteogenic growth factors BMP-2 and PDGF-BB via a fibrin-based biomaterial scaffold resulted in enhanced bone regeneration in vivo when compared to growth factors alone.…”
Section: Immunomodulation Through Targeting Pro-inflammatory Factorsmentioning
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