Biology subjects

Griffin, D.

Publications and source records attributed to Griffin, D..

6 recordsLinked to original sources

bioRxiv2026

Microporous annealed particle scaffolds avoid foreign body response by down regulating complement-fibroblast-macrophage signaling loop

Biomaterial implantation can trigger a foreign body response (FBR) that impedes tissue-implant integration. To investigate how implant porosity influences this response, we compared the immune response to subcutaneous implants of microporous annealed particle (MAP) scaffolds and nanoporous hydrogels using mass cytometry, single-cell RNA sequencing, and multiplex cytokine assays. MAP scaffolds promoted vascularization and tissue integration, marked by increased endothelial and regulatory T cells, and reduced proinflammatory immune cells and cytokines. In contrast, nanoporous hydrogels demonstrated enrichment of basophils, natural killer cells, and macrophage populations associated with fibrosis. Transcriptomic and proteomic analyses revealed that MAP scaffolds suppressed activation of the complement-fibroblast-macrophage signaling loop, particularly the C5a signaling crosstalk pathway. This was confirmed using C5-deficient mice, where complement-driven cytokine production was significantly reduced only in nanoporous implants. These findings demonstrate that scaffold porosity modulates immune and complement responses, identifying a key mechanism by which MAP scaffolds reduce FBR and improve biomaterial integration.

bioengineering↗

bioRxiv2026

Maize root system stiffness is determined by the size and distribution of the below-ground root system

Root system stiffness is a measurement associated with root lodging resistance in maize. This measurement combines contributions of root architecture, individual root-level mechanics, and root-soil interactions. In this study, we deconvolve the contribution of each of these factors to root system stiffness. Collectively, larger above- and below-ground root systems and stiffer individual brace roots contribute to a higher root system stiffness. When considering all traits in predictive models, the below-ground root architecture drives the prediction of root system stiffness categories. These below-ground traits describe the size and distribution of the root system. Analysis of a roothairless3 mutant revealed a reduction in root system stiffness primarily driven by a reduction in root size, with limited evidence for a contribution from root hairs. Together these results link root system stiffness to the size and distribution of the below-ground root system and highlight the importance of this measurement for both root lodging resistance and root phenotyping.

plant biology↗

bioRxiv2024

Cell-scale porosity in microporous annealed particle (MAP) scaffolds modulates immune response and promotes formation of innervated muscle fibers in volumetric muscle loss injuries

Volumetric muscle loss (VML) is caused by severe traumatic injuries to skeletal muscle and is characterized by the irreversible loss of contractile tissue and permanent functional deficits. VML injuries cannot be healed by endogenous mechanisms and are exceptionally difficult to treat in the clinic due to the excessive upregulation of the inflammatory response, which leads to fibrosis, denervation of muscle fibers, and impaired regeneration. These injuries lead to long-term disability. Using a rodent model of VML in the tibialis anterior, this study presents microporous annealed particle (MAP) hydrogel scaffolds as a biomaterial platform for improved muscle regeneration in VML injuries, specifically highlighting the benefits of cell-scale porosity. In contrast to bulk (i.e., nanoporous) hydrogel scaffolds, MAP scaffolds promote integration by avoiding the foreign body response, decreasing the rate of implant degradation, and shifting macrophage polarization to favor regeneration. In addition, cell migration and angiogenesis throughout the implant precede the degradation of MAP scaffolds, including the formation of muscle fibers and neuromuscular junctions within MAP scaffolds prior to degradation. These fibers and junctions continue to develop as the implant degrades, indicating that MAP hydrogel scaffolds are a promising therapeutic approach for VML injuries.

bioengineering↗

bioRxiv2022

Bcl-xL is a key mediator of apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer.

PurposeNovel covalent inhibitors of KRASG12C have shown limited response rates in KRASG12C mutant (MT) colorectal cancer (CRC) patients. Thus, novel KRASG12C inhibitor combination strategies that can achieve deep and durable responses are needed. Experimental designSmall molecule KRASG12C inhibitors AZ1569 and AZ8037 were employed. To identify novel candidate combination strategies for AZ1569, we performed RNA sequencing, siRNA and high-throughput drug screening. Top hits were validated in a panel of KRASG12CMT CRC cells and in vivo. AZ1569-resistant CRC cells were generated and characterised. ResultsResponse to AZ1569 was heterogeneous across the KRASG12CMT models. AZ1569 was ineffective at inducing apoptosis when used as single-agent or combined with chemotherapy or agents targeting the EGFR/KRAS/AKT axis. Using a systems biology approach, we identified the anti-apoptotic BH3-family member BCL2L1/Bcl-xL as a top hit mediating resistance to AZ1569. Further analyses identified acute increases in the pro-apoptotic protein BIM following AZ1569 treatment. ABT-263 (Navitoclax), a pharmacological Bcl-2 family-inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ1569. Furthermore, this combination also resulted in dramatically attenuated tumour growth in KRASG12CMT xenografts. Finally, AZ1569-resistant cells showed amplification of KRASG12C, EphA2/c-MET activation, increased pro-inflammatory chemokine profile and cross-resistance to several targeted agents. Importantly, KRAS amplification and AZ1569-resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification. ConclusionsCombinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for KRAS G12CMT CRC patients.

cancer biology↗

bioRxiv2020

Heparin MicroIslands to Promote Enhanced Diabetic Wound Healing Outcomes

A powerful tool to improve tissue integration with biomaterial scaffolds for the regeneration of damaged tissues is to promote cell migration using chemotactic gradients of growth factors. This approach has been realized by the exogenous delivery of growth factors, which unfortunately also limits the scaffolds ability to meet each wounds unique spatial and temporal regenerative needs. To address this limitation, we present a new approach to gradient generation by incorporating heparin microislands, which are spatially isolated heparin-containing microparticles that create chemotactic microgradients through reorganization of endogenous local growth factors. We incorporated heparin microislands within microporous annealed particle (MAP) scaffolds, which allows us to tune their incorporation ratiometrically to create a heterogenous microenvironment. In this manuscript, we demonstrate the ability of heparin microislands to organize uniform growth factors into spontaneous microgradients and control downstream cell migration in vitro. Further, we present their ability to significantly improve wound healing outcomes (epidermal regeneration and vascularization) in a diabetic wound model relative to two clinically relevant controls.

bioengineering↗

bioRxiv2020

The clinical and molecular significance associated with STING signaling in estrogen receptor-positive early breast cancer

STING signaling in cancer is a crucial component of response to immunotherapy and other anti-cancer treatments. Conversely, STING signaling can promote tumor invasion and metastasis. Currently, there is no robust method of measuring STING activation in cancer. Here, we describe an immunohistochemistry-based assay with digital pathology assessment of STING in tumor cells. Using this novel approach, we identify perinuclear-localized expression of STING (pnSTING) in estrogen receptor-positive (ER+) breast cancer as an independent predictor of good prognosis, associated with immune cell infiltration and upregulation of immune checkpoints. Tumors with low pnSTING are immunosuppressed with increased infiltration of "M2" -polarised macrophages. In ER-disease, pnSTING does not have a significant prognostic role, and STING appears to be uncoupled from interferon responses. Importantly, a gene signature defining low pnSTING expression in ER+ disease is predictive of poor prognosis in independent datasets. Low pnSTING is associated with chromosomal instability, MYC amplification and mTOR signaling, suggesting novel therapeutic approaches for this subgroup.

cancer biology↗