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Publications (10 of 52) Show all publications
Dennhag, N., Kahsay, A., Nissen, I., Nord, H., Chermenina, M., Liu, J., . . . Domellöf, F. P. (2024). fhl2b mediates extraocular muscle protection in zebrafish models of muscular dystrophies and its ectopic expression ameliorates affected body muscles. Nature Communications, 15(1), Article ID 1950.
Open this publication in new window or tab >>fhl2b mediates extraocular muscle protection in zebrafish models of muscular dystrophies and its ectopic expression ameliorates affected body muscles
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2024 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 15, no 1, article id 1950Article in journal (Refereed) Published
Abstract [en]

In muscular dystrophies, muscle fibers loose integrity and die, causing significant suffering and premature death. Strikingly, the extraocular muscles (EOMs) are spared, functioning well despite the disease progression. Although EOMs have been shown to differ from body musculature, the mechanisms underlying this inherent resistance to muscle dystrophies remain unknown. Here, we demonstrate important differences in gene expression as a response to muscle dystrophies between the EOMs and trunk muscles in zebrafish via transcriptomic profiling. We show that the LIM-protein Fhl2 is increased in response to the knockout of desmin, plectin and obscurin, cytoskeletal proteins whose knockout causes different muscle dystrophies, and contributes to disease protection of the EOMs. Moreover, we show that ectopic expression of fhl2b can partially rescue the muscle phenotype in the zebrafish Duchenne muscular dystrophy model sapje, significantly improving their survival. Therefore, Fhl2 is a protective agent and a candidate target gene for therapy of muscular dystrophies.

Place, publisher, year, edition, pages
Springer Nature, 2024
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-222359 (URN)10.1038/s41467-024-46187-x (DOI)38431640 (PubMedID)2-s2.0-85186557555 (Scopus ID)
Available from: 2024-03-15 Created: 2024-03-15 Last updated: 2024-03-15Bibliographically approved
Chen, J., Mo, Q., Long, Q., Sheng, R., Chen, Z., Luo, Y., . . . Zhang, W. (2023). Hydroxycamptothecin and substratum stiffness synergistically regulate fibrosis of human corneal fibroblasts. ACS Biomaterials Science & Engineering, 9(2), 959-967
Open this publication in new window or tab >>Hydroxycamptothecin and substratum stiffness synergistically regulate fibrosis of human corneal fibroblasts
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2023 (English)In: ACS Biomaterials Science & Engineering, E-ISSN 2373-9878, Vol. 9, no 2, p. 959-967Article in journal (Refereed) Published
Abstract [en]

Corneal fibrosis is a common outcome of inappropriate repair associated with trauma or ocular infection. Altered biomechanical properties with increased corneal stiffness is a feature of fibrosis that cause corneal opacities, resulting in severe visual impairment and even blindness. The present study aims to determine the effect of hydroxycamptothecin (HCPT) and matrix stiffness on transforming growth factor-β1 (TGF-β1)-induced fibrotic processes in human corneal fibroblasts (HTK cells). HTK cells were cultured on substrates with different stiffnesses ("soft", ∼261 kPa; "stiff", ∼2.5 × 103 kPa) and on tissue culture plastic (TCP, ∼106 kPa) and simultaneously treated with or without 1 μg/mL HCPT and 10 ng/mL TGF-β1. We found that HCPT induced decreased cell viability and antiproliferative effects on HTK cells. TGF-β1-induced expression of fibrosis-related genes (FN1, ACTA2) was reduced if the cells were simultaneously treated with HCPT. Substrate stiffness did not affect the expression of fibrosis-related genes. The TGF-β1 induced expression of FN1 on both soft and stiff substrates was reduced if cells were simultaneously treated with HCPT. However, this trend was not seen for ACTA2, i.e., the TGF-β1 induced expression of ACTA2 was not reduced by simultaneous treatment of HCPT in either soft or stiff substrate. Instead, HCPT treatment in the presence of TGF-β1 resulted in increased gene expression of keratocyte phenotype makers (LUM, KERA, AQP1, CHTS6) on both substrate stiffnesses. In addition, the protein expression of keratocyte phenotype makers LUM and ALDH3 was increased in HTK cells simultaneously treated with TGF-β1 and HCPT on stiff substrate as compared to control, i.e., without HCPT. In conclusion, we found that HCPT can reduce TGF-β1-induced fibrosis and promote the keratocyte phenotype in a substrate stiffness dependent manner. Thus, HCPT stimulation might be an approach to stimulate keratocytes in the appropriate healing stage to avoid or reverse fibrosis and achieve more optimal corneal wound healing.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2023
Keywords
corneal fibroblasts, HCPT, myofibroblast differentiation, substratum stiffness
National Category
Cell and Molecular Biology Ophthalmology
Identifiers
urn:nbn:se:umu:diva-204679 (URN)10.1021/acsbiomaterials.2c01302 (DOI)000926469500001 ()36705297 (PubMedID)2-s2.0-85147220511 (Scopus ID)
Available from: 2023-02-09 Created: 2023-02-09 Last updated: 2023-07-13Bibliographically approved
Sheng, R., Liu, J., Zhang, W., Luo, Y., Chen, Z., Chi, J., . . . Chen, J. (2023). Material stiffness in cooperation with macrophage paracrine signals determines the tenogenic differentiation of mesenchymal stem cells. Advanced Science, 10(17), Article ID 2206814.
Open this publication in new window or tab >>Material stiffness in cooperation with macrophage paracrine signals determines the tenogenic differentiation of mesenchymal stem cells
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2023 (English)In: Advanced Science, E-ISSN 2198-3844, Vol. 10, no 17, article id 2206814Article in journal (Refereed) Published
Abstract [en]

Stiffness is an important physical property of biomaterials that determines stem cell fate. Guiding stem cell differentiation via stiffness modulation has been considered in tissue engineering. However, the mechanism by which material stiffness regulates stem cell differentiation into the tendon lineage remains controversial. Increasing evidence demonstrates that immune cells interact with implanted biomaterials and regulate stem cell behaviors via paracrine signaling; however, the role of this mechanism in tendon differentiation is not clear. In this study, polydimethylsiloxane (PDMS) substrates with different stiffnesses are developed, and the tenogenic differentiation of mesenchymal stem cells (MSCs) exposed to different stiffnesses and macrophage paracrine signals is investigated. The results reveal that lower stiffnesses facilitates tenogenic differentiation of MSCs, while macrophage paracrine signals at these stiffnesses suppress the differentiation. When exposed to these two stimuli, MSCs still exhibit enhanced tendon differentiation, which is further elucidated by global proteomic analysis. Following subcutaneous implantation in rats for 2 weeks, soft biomaterial induces only low inflammation and promotes tendon-like tissue formation. In conclusion, the study demonstrates that soft, rather than stiff, material has a greater potential to guide tenogenic differentiation of stem cells, which provides comprehensive evidence for optimized bioactive scaffold design in tendon tissue engineering.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
macrophage polarization, proteomics, stem cell, stiffness, tenogenic differentiation
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-208058 (URN)10.1002/advs.202206814 (DOI)000975347000001 ()37097733 (PubMedID)2-s2.0-85153173993 (Scopus ID)
Available from: 2023-05-30 Created: 2023-05-30 Last updated: 2023-07-13Bibliographically approved
Li, J., Zhou, X., Chen, J., Eliasson, P., Kingham, P. J. & Backman, L. J. (2023). Secretome from myoblasts statically loaded at low intensity promotes tenocyte proliferation via the IGF-1 receptor pathway. The FASEB Journal, 37(10), Article ID e23203.
Open this publication in new window or tab >>Secretome from myoblasts statically loaded at low intensity promotes tenocyte proliferation via the IGF-1 receptor pathway
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2023 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 37, no 10, article id e23203Article in journal (Refereed) Published
Abstract [en]

Exercise is widely recognized as beneficial for tendon healing. Recently, it has been described that muscle-derived molecules secreted in response to static exercise influence tendon healing. In this study, the optimal static loading intensity for tendon healing and the composition of secretome released by myoblasts in response to different intensities of static strain were investigated. In an in vitro coculture model, myoblasts were mechanically loaded using a Flexcell Tension System. Tenocytes were seeded on transwell inserts that allowed communication between the tenocytes and myoblasts without direct contact. Proliferation and migration assays, together with RNA sequencing, were used to determine potential cellular signaling pathways. The secretome from myoblasts exposed to 2% static loading increased the proliferation and migration of the cocultured tenocytes. RNA-seq analysis revealed that this loading condition upregulated the expression of numerous genes encoding secretory proteins, including insulin-like growth factor-1 (IGF-1). Confirmation of IGF-1 expression and secretion was carried out using qPCR and enzyme-linked immunosorbt assay (ELISA), revealing a statistically significant upregulation in response to 2% static loading in comparison to both control conditions and higher loading intensities of 5% and 10%. Addition of an inhibitor of the IGF-1 receptor (PQ401) to the tenocytes significantly reduced myoblast secretome-induced tenocyte proliferation. In conclusion, IGF-1 may be an important molecule in the statically loaded myoblast secretome, which is responsible for influencing tenocytes during exercise-induced healing.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
IGF-1, mechanical loading, migration, muscle secretome, proliferation, tenocyte
National Category
Cell and Molecular Biology Physiotherapy
Identifiers
urn:nbn:se:umu:diva-214756 (URN)10.1096/fj.202301097R (DOI)37732638 (PubMedID)2-s2.0-85171800001 (Scopus ID)
Funder
Åke Wiberg Foundation, M20-0236Åke Wiberg Foundation, M22-0008The Kempe Foundations, JCK- 2032.2Swedish National Centre for Research in Sports, P2022-0010Swedish National Centre for Research in Sports, P2023-0011
Available from: 2023-10-18 Created: 2023-10-18 Last updated: 2023-10-18Bibliographically approved
Zhang, A., Zhang, W., Backman, L. J. & Chen, J. (2022). Advances in Regulatory Strategies of Differentiating Stem Cells towards Keratocytes. Stem Cells International, 2022, Article ID 5403995.
Open this publication in new window or tab >>Advances in Regulatory Strategies of Differentiating Stem Cells towards Keratocytes
2022 (English)In: Stem Cells International, ISSN 1687-9678, Vol. 2022, article id 5403995Article, review/survey (Refereed) Published
Abstract [en]

Corneal injury is a commonly encountered clinical problem which led to vision loss and impairment that affects millions of people worldwide. Currently, the available treatment in clinical practice is corneal transplantation, which is limited by the accessibility of donors. Corneal tissue engineering appears to be a promising alternative for corneal repair. However, current experimental strategies of corneal tissue engineering are insufficient due to inadequate differentiation of stem cell into keratocytes and thus cannot be applied in clinical practice. In this review, we aim to clarify the role and effectiveness of both biochemical factors, physical regulation, and the combination of both to induce stem cells to differentiate into keratocytes. We will also propose novel perspectives of differentiation strategy that may help to improve the efficiency of corneal tissue engineering.

Place, publisher, year, edition, pages
Hindawi Publishing Corporation, 2022
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-192956 (URN)10.1155/2022/5403995 (DOI)000772300700001 ()2-s2.0-85125272063 (Scopus ID)
Available from: 2022-03-07 Created: 2022-03-07 Last updated: 2023-09-05Bibliographically approved
Chen, Z., Zhang, W., Wang, M., Backman, L. J. & Chen, J. (2022). Effects of Zinc, Magnesium, and Iron Ions on Bone Tissue Engineering. ACS Biomaterials Science & Engineering, 8(6), 2321-2335
Open this publication in new window or tab >>Effects of Zinc, Magnesium, and Iron Ions on Bone Tissue Engineering
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2022 (English)In: ACS Biomaterials Science & Engineering, E-ISSN 2373-9878, Vol. 8, no 6, p. 2321-2335Article, review/survey (Refereed) Published
Abstract [en]

Large-sized bone defects are a great challenge in clinics and considerably impair the quality of patients' daily life. Tissue engineering strategies using cells, scaffolds, and bioactive molecules to regulate the microenvironment in bone regeneration is a promising approach. Zinc, magnesium, and iron ions are natural elements in bone tissue and participate in many physiological processes of bone metabolism and therefore have great potential for bone tissue engineering and regeneration. In this review, we performed a systematic analysis on the effects of zinc, magnesium, and iron ions in bone tissue engineering. We focus on the role of these ions in properties of scaffolds (mechanical strength, degradation, osteogenesis, antibacterial properties, etc.). We hope that our summary of the current research achievements and our notifications of potential strategies to improve the effects of zinc, magnesium, and iron ions in scaffolds for bone repair and regeneration will find new inspiration and breakthroughs to inspire future research.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2022
Keywords
bone, bone regeneration, iron ions, magnesium ions, scaffolds, tissue engineering, zinc ions
National Category
Medical Materials Biomaterials Science
Identifiers
urn:nbn:se:umu:diva-197503 (URN)10.1021/acsbiomaterials.2c00368 (DOI)000813798000001 ()35638755 (PubMedID)2-s2.0-85131903048 (Scopus ID)
Available from: 2022-06-30 Created: 2022-06-30 Last updated: 2023-09-05Bibliographically approved
Zhou, X., Li, J., Backman, L. J. & Danielson, P. (2022). Keratocyte Differentiation Is Regulated by NF-κB and TGFβ Signaling Crosstalk. International Journal of Molecular Sciences, 23(19), Article ID 11073.
Open this publication in new window or tab >>Keratocyte Differentiation Is Regulated by NF-κB and TGFβ Signaling Crosstalk
2022 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 19, article id 11073Article in journal (Refereed) Published
Abstract [en]

Interleukin-1 (IL-1) and transforming growth factor-beta (TGFβ) are important cytokines involved in corneal wound healing. Here, we studied the effect of these cytokines on corneal stromal cell (keratocyte) differentiation. IL-1β treatment resulted in reduced keratocyte phenotype, as evident by morphological changes and decreased expression of keratocyte markers, including keratocan, lumican, ALDH3A1, and CD34. TGFβ1 treatment induced keratocyte differentiation towards the myofibroblast phenotype. This was inhibited by simultaneous treatment with IL-1β, as seen by inhibition of α-SMA expression, morphological changes, and reduced contractibility. We found that the mechanism of crosstalk between IL-1β and TGFβ1 occurred via regulation of the NF-κB signaling pathway, since the IL-1β induced inhibition of TGFβ1 stimulated keratocyte-myofibroblast differentiation was abolished by a specific NF-κB inhibitor, TPCA-1. We further found that Smad7 participated in the downstream signaling. Smad7 expression level was negatively regulated by IL-1β and positively regulated by TGFβ1. TPCA-1 treatment led to an overall upregulation of Smad7 at mRNA and protein level, suggesting that NF-κB signaling downregulates Smad7 expression levels in keratocytes. All in all, we propose that regulation of cell differentiation from keratocyte to fibroblast, and eventually myofibroblast, is closely related to the opposing effects of IL-1β and TGFβ1, and that the mechanism of this is governed by the crosstalk of NF-κB signaling.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
corneal wound healing, IL-1, keratocyte, NF-κB, TGFβ
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-200563 (URN)10.3390/ijms231911073 (DOI)000867737100001 ()36232373 (PubMedID)2-s2.0-85139931390 (Scopus ID)
Funder
Swedish Research Council, 2017-01138Stiftelsen Kronprinsessan Margaretas arbetsnämnd för synskadade, 2013/10Umeå UniversityRegion Västerbotten, RV-930288
Available from: 2022-12-13 Created: 2022-12-13 Last updated: 2023-10-18Bibliographically approved
Prittinen, J., Zhou, X., Bano, F., Backman, L. J. & Danielson, P. (2022). Microstructured collagen films for 3D corneal stroma modelling. Connective Tissue Research, 63(5), 443-452
Open this publication in new window or tab >>Microstructured collagen films for 3D corneal stroma modelling
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2022 (English)In: Connective Tissue Research, ISSN 0300-8207, E-ISSN 1607-8438, Vol. 63, no 5, p. 443-452Article in journal (Refereed) Published
Abstract [en]

Purpose/aim: Corneal injury is a major cause of impaired vision around the globe. The fine structure of the corneal stroma plays a pivotal role in the phenotype and behavior of the embedded cells during homeostasis and healing after trauma or infection. In order to study healing processes in the cornea, it is important to create culture systems that functionally mimic the natural environment.

Materials and methods: Collagen solution was vitrified on top of a grated film to achieve thin collagen films with parallel microgrooves. Keratocytes (corneal stromal cells) were cultured on the films either as a single layer or as stacked layers of films and cells. SEM and F-actin staining were used to analyze the pattern transference onto the collagen and the cell orientation on the films. Cell viability was analyzed with MTS and live/dead staining. Keratocytes, fibroblasts, and myofibroblasts were cultured to study the pattern’s effect on phenotype.

Results: A microstructured collagen film-based culture system that guides keratocytes (stromal cells) to their native, layerwise perpendicular orientation in 3D and that can support fibroblasts and myofibroblasts was created. The films are thin and transparent enough to observe cells at least three layers deep. The cells maintain viability in 2D and 3D cultures and the films can support fibroblast and myofibroblast phenotypes.

Conclusions: The films provide an easily reproducible stroma model that maintains high cell viability and improves the preservation of the keratocyte phenotype in keratocytes that are differentiated to fibroblasts.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2022
Keywords
collagen, cornea, keratocyte, stroma, Vitrigel
National Category
Ophthalmology
Identifiers
urn:nbn:se:umu:diva-190877 (URN)10.1080/03008207.2021.2007901 (DOI)000729669400001 ()34894951 (PubMedID)2-s2.0-85121425675 (Scopus ID)
Funder
Stiftelsen Kronprinsessan Margaretas arbetsnämnd för synskadade, 2013/10Swedish Society of Medicine, 504541Swedish Research Council, 2017-01138Region Västerbotten, 549761
Available from: 2021-12-29 Created: 2021-12-29 Last updated: 2023-10-18Bibliographically approved
Mo, Q., Zhang, W., Zhu, A., Backman, L. J. & Chen, J. (2022). Regulation of osteogenic differentiation by the pro-inflammatory cytokines IL-1β and TNF-α: current conclusions and controversies. Human Cell, 35, 957-971
Open this publication in new window or tab >>Regulation of osteogenic differentiation by the pro-inflammatory cytokines IL-1β and TNF-α: current conclusions and controversies
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2022 (English)In: Human Cell, ISSN 0914-7470, Vol. 35, p. 957-971Article, review/survey (Refereed) Published
Abstract [en]

Treatment of complex bone fracture diseases is still a complicated problem that is urged to be solved in orthopedics. In bone tissue engineering, the use of mesenchymal stromal/stem cells (MSCs) for tissue repair brings hope to the medical field of bone diseases. MSCs can differentiate into osteoblasts and promote bone regeneration. An increasing number of studies show that the inflammatory microenvironment affects the osteogenic differentiation of MSCs. It is shown that TNF-α and IL-1β play different roles in the osteogenic differentiation of MSCs via different signal pathways. The main factors that affect the role of TNF-α and IL-1β in osteogenic differentiation of MSCs include concentration and the source of stem cells (different species and different tissues). This review in-depth analyzes the roles of pro-inflammatory cytokines in the osteogenic differentiation of MSCs and reveals some current controversies to provide a reference of comprehensively understanding.

Place, publisher, year, edition, pages
Springer, 2022
Keywords
IL-1β, Osteogenesis, Species differences, TNF-α
National Category
Cell and Molecular Biology Biomaterials Science
Identifiers
urn:nbn:se:umu:diva-194850 (URN)10.1007/s13577-022-00711-7 (DOI)000791657600001 ()35522425 (PubMedID)2-s2.0-85129675739 (Scopus ID)
Available from: 2022-06-07 Created: 2022-06-07 Last updated: 2022-12-05Bibliographically approved
Chi, J., Wang, M., Chen, J., Hu, L., Chen, Z., Backman, L. J. & Zhang, W. (2022). Topographic Orientation of Scaffolds for Tissue Regeneration: Recent Advances in Biomaterial Design and Applications. Biomimetics, 7(3), Article ID 131.
Open this publication in new window or tab >>Topographic Orientation of Scaffolds for Tissue Regeneration: Recent Advances in Biomaterial Design and Applications
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2022 (English)In: Biomimetics, E-ISSN 2313-7673, Vol. 7, no 3, article id 131Article, review/survey (Refereed) Published
Abstract [en]

Tissue engineering to develop alternatives for the maintenance, restoration, or enhancement of injured tissues and organs is gaining more and more attention. In tissue engineering, the scaffold used is one of the most critical elements. Its characteristics are expected to mimic the native extracellular matrix and its unique topographical structures. Recently, the topographies of scaffolds have received increasing attention, not least because different topographies, such as aligned and random, have different repair effects on various tissues. In this review, we have focused on various technologies (electrospinning, directional freeze-drying, magnetic freeze-casting, etching, and 3-D printing) to fabricate scaffolds with different topographic orientations, as well as discussed the physicochemical (mechanical properties, porosity, hydrophilicity, and degradation) and biological properties (morphology, distribution, adhesion, proliferation, and migration) of different topographies. Subsequently, we have compiled the effect of scaffold orientation on the regeneration of vessels, skin, neural tissue, bone, articular cartilage, ligaments, tendons, cardiac tissue, corneas, skeletal muscle, and smooth muscle. The compiled information in this review will facilitate the future development of optimal topographical scaffolds for the regeneration of certain tissues. In the majority of tissues, aligned scaffolds are more suitable than random scaffolds for tissue repair and regeneration. The underlying mechanism explaining the various effects of aligned and random orientation might be the differences in “contact guidance”, which stimulate certain biological responses in cells.

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
biomaterial, biomimetics, orientation, scaffold, tissue engineering, tissue regeneration, topography
National Category
Biomaterials Science
Identifiers
urn:nbn:se:umu:diva-200093 (URN)10.3390/biomimetics7030131 (DOI)000856244200001 ()36134935 (PubMedID)2-s2.0-85138617206 (Scopus ID)
Available from: 2022-10-13 Created: 2022-10-13 Last updated: 2022-10-13Bibliographically approved
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