Layla Nabai

University of British Columbia

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Aziz Ghahary

University of British Columbia

David J. Granville

University of British Columbia

Reza B. Jalili

University of British Columbia

Karen Jung

Vancouver Coastal Health Research Institute

Yunyuan Li

Longhua Hospital Shanghai University of Traditional Chinese Medicine

Ruhangiz T. Kilani

University of British Columbia

Amir Pourghadiri

University of British Columbia

Sho Hiroyasu

University of British Columbia

Richard I. Crawford

University of British Columbia

Ryan Hartwell

International Collaboration On Repair Discoveries

Cooperative Institutions

University of British Columbia

International Collaboration On Repair Discoveries

Vancouver Coastal Health Research Institute

University of British Columbia Hospital

Vancouver Coastal Health

St. Paul's Hospital

University of Alberta

Vancouver General Hospital

St. Paul's Hospital

Centre for Drug Research and Development

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SPARC/SFN interaction, suppresses type I collagen in dermal fibroblasts

Journal of Cellular Biochemistry (2012)

Claudia Chávez‐Muñoz Ryan Hartwell Reza B. Jalili Seyed Mehdi Jafarnejad Amy Lai

We previously suggested that keratinocyte releasable factors might modulate the wound healing process by regulating the expression of key extracellular matrix components such as collagenase (matrix metalloproteinase-1) and type I collagen in fibroblasts. The first one, we called it keratinocyte-derived anti-fibrogenic factor (KDAF), identified as stratifin (SFN) also named 14-3-3σ, revealing a strong collagenase activity. However, the second factor, which we named keratinocyte-derived collagen-inhibiting factor(s) (KD-CIF) that has shown to control the synthesis of type I collagen, was not known. Upon conducting a series of systematic protein purification methods followed by mass spectroscopy, two proteins: secreted protein acidic rich in cystein (SPARC) and SFN were identified in keratinocyte-conditioned media. Using co-immunoprecipitation and 3D modeling, we determined that SFN and SPARC form a complex thereby controlling the type I collagen synthesis and expression in fibroblasts. The levels of these proteins in fibrotic tissues (animal and human) were also evaluated and a differential expression of these proteins between normal and fibrotic tissue confirmed their potential role in development of fibrotic condition. In conclusion, this study describes for the first time an interaction between SPARC and SFN that may have implications for the regulation of matrix deposition and prevention of dermal fibrotic conditions such as hypertrophic scars and keloid.

Keloid

Type I collagen

Matrix (chemical analysis)

10.1002/jcb.24137

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Citations (16)

Immunoprotective Role of Indoleamine 2,3-Dioxygenase in Engraftment of Allogenic Skin Substitute in Wound Healing

Journal of Burn Care & Research (2012)

Mohammad Ali Bahar Layla Nabai Aziz Ghahary

Delayed wound healing can significantly impact survival of patients who suffer from severe thermal injury. In general, the use of a wound coverage, particularly with those of bilayer skin substitute, would be ideal to promote healing and prevent infection and fluid loss. Although the use of an autologous skin substitute is desirable, its preparation is time consuming and its immediate availability is impossible. To overcome this difficulty, the authors have previously demonstrated that the expression of indoleamine 2,3 dioxygenase (IDO) could function as a local immune suppressive factor in protecting allogenic fibroblasts and keratinocytes without using any immunosuppressive medication in a wound healing animal model. IDO, which is naturally expressed in the placenta by trophoblast cells during pregnancy, plays an essential role in maternal tolerance toward the fetus. The potent and selective local immunosuppressive function of IDO makes this enzyme a very promising tool for engineering a nonrejectable skin allograft. Here, the authors reviewed and discussed how the expression of IDO by the primary cells of our skin substitute can serve as a source of IDO enzyme activity and generate a tryptophan-deficient environment. Under this condition, only skin cells but not immune cells (CD4+ and CD8+ cells) would survive and protect engraftment of this engineered and shelf-ready skin substitute to be used not only as wound coverage but also as a rich source of wound healing promoting factors. Therefore, this review summarizes the body of work on immunoprotective role of IDO in engraftment of allogenic skin substitute in wound healing, which has recently been reported by the authors' research group and others.

Indoleamine 2,3-dioxygenase

10.1097/bcr.0b013e318235836e

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Citations (14)

Efficacy of kynurenic acid and methotrexate in prevention of fibrosis

Layla Nabai

Kynurenic acid

10.14288/1.0380513

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Citations (0)

A novel hydrogel-collagen composite improves functionality of an injectable extracellular matrix

Acta Biomaterialia (2011)

Ryan Hartwell Victor C. M. Leung Claudia Chávez‐Muñoz Layla Nabai Heejae Yang

Matrix (chemical analysis)

10.1016/j.actbio.2011.04.024

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Citations (47)

A CASE REPORT OF CHRONIC MUCOCUTANEOUS CANDIDIASIS IN IRAN

DOAJ (DOAJ: Directory of Open Access Journals) (1991)

Mohsen Moghaddami Mas Ud Emami P. Toosi Layla Nabai

A case of chronic mucocutaneous candidiasis due to Candida albicans in a 13 yr-old boy is reported. Evaluation of cell mediated immunity revealed cutaneous anergy to PPD and low level of T-Lymphocytes B-Cell count and immunoglobulin G (IgG) were increased and there was a low level of serum iron. The patient was put under treatment with oral administration of Ketoconazole and ferrus sulfate, which resulted in some clinical improvement

Chronic mucocutaneous candidiasis

Mucocutaneous zone

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Hypertrophic Scarring in the Rabbit Ear: A Practical Model for Studying Dermal Fibrosis

Methods in molecular biology (2017)

Layla Nabai Aziz Ghahary

Hypertrophic scars

Animal model

10.1007/978-1-4939-7113-8_6

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Citations (19)

Granzyme B cleaves Tenascin-C to release its C-terminal domain in rheumatoid arthritis

JCI Insight (2024)

Alexandre Aubert Amy Liu Martin Kao Jenna Goeres Katlyn C. Richardson

Rheumatoid arthritis (RA) is one of the most common autoimmune disorders and is characterized by exacerbated joint inflammation that can lead to tissue remodeling and autoantigen generation. Despite the well-documented accumulation of the serine protease Granzyme B (GzmB) in the biospecimens of patients with RA, little is understood pertaining to its role in pathobiology. In the present study Tenascin-C (TN-C), a large extracellular matrix glycoprotein and an endogenous trigger of inflammation, was identified as a substrate for GzmB in RA. GzmB cleaves TN-C in vitro to generate three fragments: a 130 kDa fragment that remains anchored to the matrix, and two 70 and 30 kDa fragments that are released and solubilized. Mass spectrometry results seem to indicate that the 30 kDa fragment generated by GzmB most likely contains TN-C pro-inflammatory C-terminal fibrinogen-like domain. Soluble levels of GzmB and TN-C are also significantly elevated in the synovial fluids of RA patients compared to healthy controls, with two 70 kDa and 30 kDa soluble TN-C fragments detectable in the synovial fluids of RA patients. The molecular weights of these fragments coincide with those generated by GzmB in vitro, suggesting that GzmB also cleaves TN-C in RA patients. Granzyme K (GzmK), another member of the granzyme family, also cleaves TN-C in vitro. However, unlike GzmB, the molecular weights of TN-C fragments generated by GzmK in vitro do not correspond to fragments identified in patients. Altogether, our data supports the contribution of Granzyme B, but not Granzyme K, to RA through the cleavage of Tenascin-C.

Granzyme

10.1172/jci.insight.181935

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Citations (1)

Localized Controlled Release of Kynurenic Acid Encapsulated in Synthetic Polymer Reduces Implant—Induced Dermal Fibrosis

Pharmaceutics (2022)

Layla Nabai Aziz Ghahary John K. Jackson

Excessive fibrosis following surgical procedures is a challenging condition with serious consequences and no effective preventive or therapeutic option. Our group has previously shown the anti-fibrotic effect of kynurenic acid (KynA) in vitro and as topical cream formulations or nanofiber dressings in open wounds. Here, we hypothesized that the implantation of a controlled release drug delivery system loaded with KynA in a wound bed can prevent fibrosis in a closed wound. Poly (lactic-co-glycolic acid) (PLGA), and a diblock copolymer, methoxy polyethylene glycol-block-poly (D, L-lactide) (MePEG-b-PDLLA), were used for the fabrication of microspheres which were evaluated for their characteristics, encapsulation efficiency, in vitro release profile, and in vivo efficacy for reduction of fibrosis. The optimized formulation exhibited high encapsulation efficiency (>80%), low initial burst release (~10%), and a delayed, gradual release of KynA. In vivo evaluation of the fabricated microspheres in the PVA model of wound healing revealed that KynA microspheres effectively reduced collagen deposition inside and around PVA sponges and α-smooth muscle actin expression after 66 days. Our results showed that KynA can be efficiently encapsulated in PLGA microspheres and its controlled release in vivo reduces fibrotic tissue formation, suggesting a novel therapeutic option for the prevention or treatment of post-surgical fibrosis.

PLGA

Kynurenic acid

10.3390/pharmaceutics14081546

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Citations (9)

Novel, Blended Polymeric Microspheres for the Controlled Release of Methotrexate: Characterization and In Vivo Antifibrotic Studies

Bioengineering (2023)

Layla Nabai Aziz Ghahary John K. Jackson

Low dose methotrexate (MTX) is known to effectively decrease type I collagen production in dermal fibroblasts, while increasing the matrix metalloproteinase-1 (MMP-1) production in vitro. For in vivo use as an antifibrotic agent on wounds, a linear and extended controlled release formulation of MTX is required. The objective of this study was to optimize the fabrication of MTX-loaded polymeric microspheres with such properties, and to test the efficacy for the prevention of fibrosis in vivo. Poly lactic-co-glycolic acid (PLGA), Poly (L-lactic acid) (PLLA) and the diblock copolymer, methoxypolyethylene glycol-block-poly (D, L-lactide) (MePEG-b-PDLLA), were used to fabricate microspheres, which were then characterized in terms of size, drug encapsulation efficiency, and in vitro release profiles. The optimized formulation (PLGA with diblock copolymer) showed high drug encapsulation efficiency (>80%), low burst release (~10%) and a gradual release of MTX. The amphipathic diblock copolymer is known to render the microsphere surface more biocompatible. In vivo, these microspheres were effective in reducing fibrotic tissue which was confirmed by quantitative measurement of type I collagen and α-smooth muscle actin expression, demonstrating that MTX can be efficiently encapsulated in PLGA microspheres to provide a delayed, gradual release in wound beds to reduce fibrosis in vivo.

PLGA

10.3390/bioengineering10030298

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Citations (3)

Evaluation of Detergent-Free and Detergent-Based Methods for Decellularization of Murine Skin

Tissue Engineering Part A (2018)

Ali Farrokhi Mohammadreza Pakyari Layla Nabai Amir Pourghadiri Ryan Hartwell

Acute and chronic wounds contribute to increased morbidity and mortality in affected people and impose significant financial burdens on healthcare systems. For these challenging wounds, acellular dermal matrices (ADMs) have been used as a biological wound coverage. Unlike engineered dermal matrices, ADMs are prepared through the removal of cells from skin, while preserving the extracellular matrix structure and function. In this study, our primary objective was to develop a detergent-free method for decellularization of the skin to mitigate chemical stress on matrix molecules. Then, we performed a set of in vitro and in vivo experiments to compare this method with nonionic and anionic detergent methods. All decellularization methods satisfactorily removed cells and supported fibroblast growth and migration in vitro. Sulfated glycosaminoglycan content was reduced significantly (p < 0.05) only in the ionic detergent treatment group. In contrast to the detergent-free method, all detergent-based methods significantly reduced scaffold mechanical strength and elastin content (p < 0.05). Three weeks after transplantation, the results showed reepithelialization, angiogenesis, and migration of host cell into scaffolds with no induction of immunogenic reaction in all ADM groups tested. In our study, the detergent-free method showed better preservation of matrix composition and biomechanical properties, but after transplantation, all methods of ADM preparation resulted in equally biofunctional matrices as wound coverage.

Decellularization

Matrix (chemical analysis)

10.1089/ten.tea.2017.0273

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Citations (31)