Delivery of A Jagged1-PEG-MAL hydrogel with Pediatric Human Bone Cells Regenerates Critically-Sized Craniofacial Bone Defects
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Curated by eLife
eLife assessment
Therapeutic treatments for congenital and acquired craniofacial (CF) bone abnormalities are not well developed. This study provides convincing evidence for an innovative regenerative treatment for pediatric craniofacial bone loss using Jagged1-PEG-MAL hydrogel with pediatric human bone cells. The report is a valuable advance in this field.
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Abstract
Treatments for congenital and acquired craniofacial (CF) bone abnormalities are limited and expensive. Current reconstructive methods include surgical correction of injuries, short-term bone stabilization, and long-term use of bone grafting solutions, including implantation of (i) allografts which are prone to implant failure or infection, (ii) autografts which are limited in supply. Current bone regenerative approaches have consistently relied on BMP-2 application with or without addition of stem cells. BMP2 treatment can lead to severe bony overgrowth or uncontrolled inflammation, which can accelerate further bone loss. Bone marrow-derived mesenchymal stem cell-based treatments, which do not have the side effects of BMP2, are not currently FDA approved, and are time and resource intensive. There is a critical need for novel bone regenerative therapies to treat CF bone loss that have minimal side effects, are easily available, and are affordable. In this study we investigated novel bone regenerative therapies downstream of JAGGED1 (JAG1).We previously demonstrated that JAG1 induces murine cranial neural crest (CNC) cells towards osteoblast commitment via a NOTCH non-canonical pathway involving JAK2-STAT5 (1) and that JAG1 delivery with CNC cells elicits bone regeneration in vivo. In this study, we hypothesized that delivery of JAG1 and induction of its downstream NOTCH non-canonical signaling in pediatric human osteoblasts constitute an effective bone regenerative treatment in an in vivo murine bone loss model of a critically-sized cranial defect. Using this CF defect model in vivo , we delivered JAG1 with pediatric human bone-derived osteoblast-like (HBO) cells to demonstrate the osteo-inductive properties of JAG1 in human cells and in vitro we utilized the HBO cells to identify the downstream non-canonical JAG1 signaling intermediates as effective bone regenerative treatments. In vitro, we identified an important mechanism by which JAG1 induces pediatric osteoblast commitment and bone formation involving the phosphorylation of p70 S6K. This discovery enables potential new treatment avenues involving the delivery of tethered JAG1 and the downstream activators of p70 S6K as powerful bone regenerative therapies in pediatric CF bone loss.
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eLife assessment
Therapeutic treatments for congenital and acquired craniofacial (CF) bone abnormalities are not well developed. This study provides convincing evidence for an innovative regenerative treatment for pediatric craniofacial bone loss using Jagged1-PEG-MAL hydrogel with pediatric human bone cells. The report is a valuable advance in this field.
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Reviewer #1 (Public Review):
Summary:
In this manuscript, the authors introduced a compelling study that explored an innovative regenerative treatment for pediatric craniofacial bone loss, with a particular focus on investigating the impacts of JAGGED1 (JAG1) signaling.
Strengths:
Building on their prior research involving the effect of JAG1 on murine cranial neural crest cells, the authors demonstrated successful bone regeneration in an in vivo murine bone loss model with a critically-sized cranial defect, where they delivered JAG1 with pediatric human bone-derived osteoblast-like cells in the hydrogel. Additionally, their findings unveiled a crucial mechanism wherein JAG1 induces pediatric osteoblast commitment and bone regeneration through the phosphorylation of p70 S6K. This discovery offers a promising avenue for potential …
Reviewer #1 (Public Review):
Summary:
In this manuscript, the authors introduced a compelling study that explored an innovative regenerative treatment for pediatric craniofacial bone loss, with a particular focus on investigating the impacts of JAGGED1 (JAG1) signaling.
Strengths:
Building on their prior research involving the effect of JAG1 on murine cranial neural crest cells, the authors demonstrated successful bone regeneration in an in vivo murine bone loss model with a critically-sized cranial defect, where they delivered JAG1 with pediatric human bone-derived osteoblast-like cells in the hydrogel. Additionally, their findings unveiled a crucial mechanism wherein JAG1 induces pediatric osteoblast commitment and bone regeneration through the phosphorylation of p70 S6K. This discovery offers a promising avenue for potential treatment, involving targeted delivery of JAG1 and activation of downstream p70 s6K, for pediatric craniofacial bone loss. Overall, the experimental design is appropriate, and the results are clearly presented.
Weaknesses:
Several methodology details need to be clearly included and gender differences should be evaluated and discussed.
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Reviewer #2 (Public Review):
The current manuscript undoubtedly demonstrates that JAG1 can induce osteogenesis via non-canonical signaling. Using the mouse-calvarial critical defect model, the authors have clearly shown the anabolic regenerative effect of JAG1 via non-canonical pathways. Exploring the molecular mechanisms, the authors have shown that non-canonically JAG1 regulates multiple pathways including STAT5, AKT, P38, JNK, NF-ĸB, and p70 S6K, which together possibly culminate in the activation of p70 S6K. More analysis is required to strongly conclude the role of the JAG1-p70 S6K pathway in the process. In summary, these findings have significant implications for designing new approaches for bone regenerative research.
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