Publications
Research articles, reviews, book chapters
2024
- Decoding the complexity of delayed wound healing following Enterococcus faecalis infectionC. Celik, S. Y. T. Lee, F. R. Tanoto, M. Veleba, K. Kline, and G. ThibaultMay 2024
Wound infections are highly prevalent and can lead to delayed or failed healing, causing significant morbidity and adverse economic impacts. These infections occur in various contexts, including diabetic foot ulcers, burns, and surgical sites. Enterococcus faecalis is often found in persistent non-healing wounds, but its contribution to chronic wounds remains understudied. To address this, we employed single-cell RNA sequencing (scRNA-seq) on infected wounds in comparison to uninfected wounds in a mouse model. Examining over 23,000 cells, we created a comprehensive single-cell atlas that captures the cellular and transcriptomic landscape of these wounds. Our analysis revealed unique transcriptional and metabolic alterations in infected wounds, elucidating the distinct molecular changes associated with bacterial infection compared to the normal wound healing process. We identified dysregulated keratinocyte and fibroblast transcriptomes in response to infection, jointly contributing to an anti-inflammatory environment. Notably, E. faecalis infection prompted a premature, incomplete epithelial-mesenchymal transition in keratinocytes. Additionally, E. faecalis infection modulated M2-like macrophage polarization by inhibiting pro-inflammatory resolution in vitro, in vivo, and in our scRNA-seq atlas. Furthermore, we discovered macrophage crosstalk with neutrophils, which regulates chemokine signaling pathways, while promoting anti-inflammatory interactions with endothelial cells. Overall, our findings offer new insights into the immunosuppressive role of E. faecalis in wound infections.
@article{Celik2024, article_type = {journal}, title = {Decoding the complexity of delayed wound healing following Enterococcus faecalis infection}, author = {Celik, C. and Lee, S. Y. T. and Tanoto, F. R. and Veleba, M. and Kline, K. and Thibault, G.}, editor = {Vance, Russell E and Rath, Satyajit}, volume = {13}, year = {2024}, month = may, pub_date = {2024-05-20}, pages = {RP95113}, citation = {eLife 2024;13:RP95113}, doi = {10.7554/eLife.95113}, journal = {eLife}, issn = {2050-084X}, publisher = {eLife Sciences Publications, Ltd}, type = {Journal Article}, } - Genetic regulation of injury induced heterotopic ossification in adult zebrafishA. K. Kaliya-Perumal, C. Celik, T. J. Carney, M. P. Harris, and P. W. InghamMay 2024
Heterotopic ossification is the inappropriate formation of bone in soft tissues of the body. It can manifest spontaneously in rare genetic conditions or as a response to injury, known as acquired heterotopic ossification. There are several experimental models for studying acquired heterotopic ossification from different sources of damage. However, their tenuous mechanistic relevance to the human condition, invasive and laborious nature and/or lack of amenability to chemical and genetic screens, limit their utility. To address these limitations, we developed a simple zebrafish injury model that manifests heterotopic ossification with high penetrance in response to clinically-emulating injuries as observed in human myositis ossificans traumatica. Exploiting this model, we defined the transcriptional response to trauma, identifying differentially regulated genes. Mutant analyses revealed that an increase in potassium channel Kcnk5b activity potentiates injury response, while loss of interleukin 11 receptor paralogue (Il11ra) function resulted in a drastically reduced ossification response. Based on these findings, we postulate that enhanced ionic signalling, specifically through Kcnk5b, regulates the intensity of the skeletogenic injury response, which, in part, requires immune response regulated by Il11ra.
@article{10.1242/dmm.050724, author = {Kaliya-Perumal, A. K. and Celik, C. and Carney, T. J. and Harris, M. P. and Ingham, P. W.}, title = {{Genetic regulation of injury induced heterotopic ossification in adult zebrafish}}, journal = {Disease Models & Mechanisms}, pages = {dmm.050724}, year = {2024}, month = may, issn = {1754-8403}, doi = {10.1242/dmm.050724}, type = {Journal Article}, }
2023
- Endoplasmic reticulum stress and lipids in health and diseasesC. Celik, S. Y. T. Lee, W. S. Yap, and G. ThibaultMay 2023
The endoplasmic reticulum (ER) is a complex and dynamic organelle that regulates many cellular pathways, including protein synthesis, protein quality control, and lipid synthesis. When one or multiple ER roles are dysregulated and saturated, the ER enters a stress state, which, in turn, activates the highly conserved unfolded protein response (UPR). By sensing the accumulation of unfolded proteins or lipid bilayer stress (LBS) at the ER, the UPR triggers pathways to restore ER homeostasis and eventually induces apoptosis if the stress remains unresolved. In recent years, it has emerged that the UPR works intimately with other cellular pathways to maintain lipid homeostasis at the ER, and so does at cellular levels. Lipid distribution, along with lipid anabolism and catabolism, are tightly regulated, in part, by the ER. Dysfunctional and overwhelmed lipid-related pathways, independently or in combination with ER stress, can have reciprocal effects on other cellular functions, contributing to the development of diseases. In this review, we summarize the current understanding of the UPR in response to proteotoxic stress and LBS and the breadth of the functions mitigated by the UPR in different tissues and in the context of diseases.
@article{Celik2023, author = {Celik, C. and Lee, S. Y. T. and Yap, W. S. and Thibault, G.}, title = {Endoplasmic reticulum stress and lipids in health and diseases}, journal = {Progress in Lipid Research}, volume = {89}, pages = {101198}, issn = {1873-2194 (Electronic) 0163-7827 (Linking)}, doi = {10.1016/j.plipres.2022.101198}, year = {2023}, type = {Journal Article}, }
2022
- The unfolded protein response reverses the effects of glucose on lifespan in chemically-sterilized C. elegansC. Beaudoin-Chabot, L. Wang, C. Celik, A. T. Abdul Khalid, S. Thalappilly, S. Xu, J. H. Koh, V. W. X. Lim, A. D. Low, and G. ThibaultMay 2022
Metabolic diseases often share common traits, including accumulation of unfolded proteins in the endoplasmic reticulum (ER). Upon ER stress, the unfolded protein response (UPR) is activated to limit cellular damage which weakens with age. Here, we show that Caenorhabditis elegans fed a bacterial diet supplemented high glucose at day 5 of adulthood (HGD-5) extends their lifespan, whereas exposed at day 1 (HGD-1) experience shortened longevity. We observed a metabolic shift only in HGD-1, while glucose and infertility synergistically prolonged the lifespan of HGD-5, independently of DAF-16. Notably, we identified that UPR stress sensors ATF-6 and PEK-1 contributed to the longevity of HGD-5 worms, while ire-1 ablation drastically increased HGD-1 lifespan. Together, we postulate that HGD activates the otherwise quiescent UPR in aged worms to overcome ageing-related stress and restore ER homeostasis. In contrast, young animals subjected to HGD provokes unresolved ER stress, conversely leading to a detrimental stress response.
@article{Beaudoin2022, author = {Beaudoin-Chabot, C. and Wang, L. and Celik, C. and Abdul Khalid, A. T. and Thalappilly, S. and Xu, S. and Koh, J. H. and Lim, V. W. X. and Low, A. D. and Thibault, G.}, title = {The unfolded protein response reverses the effects of glucose on lifespan in chemically-sterilized C. elegans}, journal = {Nature Communications}, volume = {13}, number = {1}, pages = {5889}, issn = {2041-1723 (Electronic) 2041-1723 (Linking)}, doi = {10.1038/s41467-022-33630-0}, year = {2022}, type = {Journal Article}, } - Neuronal IRE-1 coordinates an organism-wide cold stress response by regulating fat metabolismR. Dudkevich, J. H. Koh, C. Beaudoin-Chabot, C. Celik, I. Lebenthal-Loinger, S. Karako-Lampert, S. Ahmad-Albukhari, G. Thibault, and S. Henis-KorenblitMay 2022
Cold affects many aspects of biology, medicine, agriculture, and industry. Here, we identify a conserved endoplasmic reticulum (ER) stress response, distinct from the canonical unfolded protein response, that maintains lipid homeostasis during extreme cold. We establish that the ER stress sensor IRE-1 is critical for resistance to extreme cold and activated by cold temperature. Specifically, neuronal IRE-1 signals through JNK-1 and neuropeptide signaling to regulate lipid composition within the animal. This cold-response pathway can be bypassed by dietary supplementation with unsaturated fatty acids. Altogether, our findings define an ER-centric conserved organism-wide cold stress response, consisting of molecular neuronal sensors, effectors, and signaling moieties, which control adaptation to cold conditions in the organism. Better understanding of the molecular basis of this stress response is crucial for the optimal use of cold conditions on live organisms and manipulation of lipid saturation homeostasis, which is perturbed in human pathologies.
@article{Dudkevich2022, author = {Dudkevich, R. and Koh, J. H. and Beaudoin-Chabot, C. and Celik, C. and Lebenthal-Loinger, I. and Karako-Lampert, S. and Ahmad-Albukhari, S. and Thibault, G. and Henis-Korenblit, S.}, title = {Neuronal IRE-1 coordinates an organism-wide cold stress response by regulating fat metabolism}, journal = {Cell Reports}, volume = {41}, number = {9}, pages = {111739}, issn = {2211-1247 (Electronic)}, doi = {10.1016/j.celrep.2022.111739}, year = {2022}, type = {Journal Article}, }
2021
- Directionalities of magnetic fields and topographic scaffolds synergise to enhance MSC chondrogenesisC. Celik, A. Franco-Obregón, E. H. Lee, J. H. Hui, and Z. YangMay 2021
Mesenchymal stem cell (MSC) chondrogenesis is modulated by diverse biophysical cues. We have previously shown that brief, low-amplitude pulsed electromagnetic fields (PEMFs) differentially enhance MSC chondrogenesis in scaffold-free pellet cultures versus conventional tissue culture plastic (TCP), indicating an interplay between magnetism and micromechanical environment. Here, we examined the influence of PEMF directionality over the chondrogenic differentiation of MSCs laden on electrospun fibrous scaffolds of either random (RND) or aligned (ALN) orientations. Correlating MSCs’ chondrogenic outcome to pFAK activation and YAP localisation, MSCs on the RND scaffolds experienced the least amount of resting mechanical stress and underwent greatest chondrogenic differentiation in response to brief PEMF exposure (10 min at 1 mT) perpendicular to the dominant plane of the scaffolds (Z-directed). By contrast, in MSC-impregnated RND scaffolds, greatest mitochondrial respiration resulted from X-directed PEMF exposure (parallel to the scaffold plane), and was associated with curtailed chondrogenesis. MSCs on TCP or the ALN scaffolds exhibited greater resting mechanical stress and accordingly, were unresponsive, or negatively responsive, to PEMF exposure from all directions. The efficacy of PEMF-induced MSC chondrogenesis is hence regulated in a multifaceted manner involving focal adhesion dynamics, as well as mitochondrial responses, culminating in a final cellular response. The combined contributions of micromechanical environment and magnetic field orientation hence will need to be considered when designing magnetic exposure paradigms.
@article{Celik2021, author = {Celik, C. and Franco-Obregón, A. and Lee, E. H. and Hui, J. H. and Yang, Z.}, title = {Directionalities of magnetic fields and topographic scaffolds synergise to enhance MSC chondrogenesis}, journal = {Acta Biomaterialia}, volume = {119}, pages = {169-183}, issn = {1878-7568 (Electronic) 1742-7061 (Linking)}, doi = {10.1016/j.actbio.2020.10.039}, year = {2021}, type = {Journal Article}, }
2020
- Pulsed electromagnetic fields potentiate the paracrine function of mesenchymal stem cells for cartilage regenerationD. Parate, N. D. Kadir, C. Celik, E. H. Lee, J. H. P. Hui, A. Franco-Obregón, and Z. YangMay 2020
BACKGROUND: The mesenchymal stem cell (MSC) secretome, via the combined actions of its plethora of biologically active factors, is capable of orchestrating the regenerative responses of numerous tissues by both eliciting and amplifying biological responses within recipient cells. MSCs are "environmentally responsive" to local micro-environmental cues and biophysical perturbations, influencing their differentiation as well as secretion of bioactive factors. We have previously shown that exposures of MSCs to pulsed electromagnetic fields (PEMFs) enhanced MSC chondrogenesis. Here, we investigate the influence of PEMF exposure over the paracrine activity of MSCs and its significance to cartilage regeneration. METHODS: Conditioned medium (CM) was generated from MSCs subjected to either 3D or 2D culturing platforms, with or without PEMF exposure. The paracrine effects of CM over chondrocytes and MSC chondrogenesis, migration and proliferation, as well as the inflammatory status and induced apoptosis in chondrocytes and MSCs was assessed. RESULTS: We show that benefits of magnetic field stimulation over MSC-derived chondrogenesis can be partly ascribed to its ability to modulate the MSC secretome. MSCs cultured on either 2D or 3D platforms displayed distinct magnetic sensitivities, whereby MSCs grown in 2D or 3D platforms responded most favorably to PEMF exposure at 2 mT and 3 mT amplitudes, respectively. Ten minutes of PEMF exposure was sufficient to substantially augment the chondrogenic potential of MSC-derived CM generated from either platform. Furthermore, PEMF-induced CM was capable of enhancing the migration of chondrocytes and MSCs as well as mitigating cellular inflammation and apoptosis. CONCLUSIONS: The findings reported here demonstrate that PEMF stimulation is capable of modulating the paracrine function of MSCs for the enhancement and re-establishment of cartilage regeneration in states of cellular stress. The PEMF-induced modulation of the MSC-derived paracrine function for directed biological responses in recipient cells or tissues has broad clinical and practical ramifications with high translational value across numerous clinical applications.
@article{Parate2020, author = {Parate, D. and Kadir, N. D. and Celik, C. and Lee, E. H. and Hui, J. H. P. and Franco-Obregón, A. and Yang, Z.}, title = {Pulsed electromagnetic fields potentiate the paracrine function of mesenchymal stem cells for cartilage regeneration}, journal = {Stem Cell Research and Therapy}, volume = {11}, number = {1}, pages = {46}, issn = {1757-6512 (Electronic) 1757-6512 (Linking)}, doi = {10.1186/s13287-020-1566-5}, year = {2020}, type = {Journal Article}, }
2019
- Preparation of electrospun polycaprolactone nanofiber mats loaded with microalgal extractsS. D. Cetmi, N. Z. Renkler, A. Kose, C. Celik, and S. S. OncelMay 2019
Sustainable, ecological, and biocompatible materials are emerging for the development of novel components for tissue engineering. Microalgae being one of the unique organisms on Earth to provide various novel compounds with certain bioactivities are also a good source for the development of novel tissue scaffold materials. In this study, electrospinning technique was utilized to fabricate nanofibers from polycaprolactone loaded with microalgal extracts obtained from Haematococcus pluvialis (vegetative and carotenoid producing form) and Chlorella vulgaris. The FTIR results showed that, blending microalgae with polycaprolactone give unique bands rooted from microalgae and polycaprolactone structure. The samples were not diversified from each other, however stable bands were observed. SEM analysis revealed a uniform fiber fabrication with an average diameter of 810 +/- 55 nm independent from microalgal extracts. MTT assay was done on HUVEC cell lines and results showed that nanofiber mats helped cell proliferation with extended time. Biodegradation resulted with mineral accumulation on the surface of same samples however the fiber degradation was uniform. With slow but stable biodegradation characteristics, microalgal extract loaded nanofiber mats holds great potential to be novel tissue scaffold material.
@article{Cetmi2019, author = {Cetmi, S. D. and Renkler, N. Z. and Kose, A. and Celik, C. and Oncel, S. S.}, title = {Preparation of electrospun polycaprolactone nanofiber mats loaded with microalgal extracts}, journal = {Engineering in Life Sciences}, volume = {19}, number = {10}, pages = {691-699}, issn = {1618-0240 (Print) 1618-2863 (Electronic) 1618-0240 (Linking)}, doi = {10.1002/elsc.201900009}, year = {2019}, type = {Journal Article} }
2018
- Injectable Hydrogels for Cartilage RegenerationC. Celik, V. T. Mogal, J. H. P. Hui, X. J. Loh, and W. S. TohMay 2018
Articular cartilage injuries have a limited potential to heal, which over time, may lead to osteoarthritis, an inflammatory and degenerative joint disease associated with activity-related pain, swelling, and impaired mobility. Regeneration and restoration of joint tissue and function remain unmet challenges. Intra-articular injections of therapeutic agents are effective to some extent, but often require multiple injections. In the past decade, injectable hydrogels have emerged as promising biomaterials, due largely to their biocompatibility, tissue extracellular matrix (ECM) mimicry, excellent permeability, and easy adaptation for minimal-invasive procedures. Moreover, hydrogels can be designed as carriers for sustained release of therapeutic agents and protective matrices for cell delivery. This chapter provides an overview of the injectable hydrogel systems currently being applied together with therapeutic drug delivery and/or cell therapy for treatment of cartilage lesions and osteoarthritis.
@inbook{Celik2018, author = {Celik, C. and Mogal, V. T. and Hui, J. H. P. and Loh, X. J. and Toh, W. S.}, title = {Injectable Hydrogels for Cartilage Regeneration}, booktitle = {Hydrogels: Recent Advances}, editor = {Thakur, V. K. and Thakur, M. K.}, series = {Gels Horizons: From Science to Smart Materials}, chapter = {Chapter 12}, pages = {315-337}, publisher = {Springer Singapore}, isbn = {978-981-10-6076-2, 978-981-10-6077-9}, doi = {10.1007/978-981-10-6077-9_12}, year = {2018}, type = {Book Section}, }
2016
- Self-Assembled Biomimetic Scaffolds for Bone Tissue EngineeringO. Karaman, C. Celik, and A. SendemirMay 2016
Cranial, maxillofacial, and oral fractures, as well as large bone defects, are currently being treated by auto- and allograft procedures. These techniques have limitations such as immune response, donor-site morbidity, and lack of availability. Therefore, the interest in tissue engineering applications as replacement for bone graft has been growing rapidly. Typical bone tissue engineering models require a cell-supporting scaffold in order to maintain a 3-dimensional substrate mimicking in vivo extracellular matrix for cells to attach, proliferate and function during the formation of bone tissue. Combining the understanding of molecular and structural biology with materials engineering and design will enable new strategies for developing biological tissue constructs with clinical relevance. Self-assembled biomimetic scaffolds are especially suitable as they provide spatial and temporal regulation. Specifically, self-assembling peptides capable of in situ gelation serve as attractive candidates for minimally invasive injectable therapies in bone tissue engineering applications.
@inbook{Karaman2016, author = {Karaman, O. and Celik, C. and Sendemir, A.}, title = {Self-Assembled Biomimetic Scaffolds for Bone Tissue Engineering}, booktitle = {Emerging Research on Bioinspired Materials Engineering}, editor = {Bououdina, Mohamed}, publisher = {IGI Global}, address = {Hershey, PA, USA}, pages = {104-132}, isbn = {9781466698116}, doi = {10.4018/978-1-4666-9811-6.ch004}, year = {2016}, type = {Book Section}, }