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Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0
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Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 August 2023) | Viewed by 31124

Special Issue Editors

Prof. Dr. Magali Cucchiarini

E-Mail Website
Guest Editor
Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, D-66421 Homburg, Saar, Germany
Interests: molecular gene therapy; human regenerative medicine; tissue engineering; musculoskeletal research; stem cells
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Henning Madry

E-Mail Website
Guest Editor
Center of Experimental Orthopaedics, Saarland University Medical Center, Kirrbergerstr. Bldg 37, D-66421 Homburg, Saar, Germany
Interests: human musculoskeletal disorders; clinical orthopaedics; animal models; human regenerative medicine
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our previous Special Issues: “Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine”; (https://www.mdpi.com/journal/ijms/special_issues/musculoskeletal_reg), “Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 2.0”; (https://www.mdpi.com/journal/ijms/special_issues/musculoskeletal_reg2) and “Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 3.0” (https://www.mdpi.com/journal/ijms/special_issues/musculoskeletal_reg3).

Injuries affecting the various tissues of the musculoskeletal system (articular cartilage, bone, meniscus, and tendons/ligaments) do not fully heal by themselves due to a limited or unsatisfactory ability of these tissues to spontaneously repair themselves. While a number of clinical options are available to address such problems, none is capable of reproducing the native tissue structures and original functions of patients, showing the vital need for novel alternatives that may improve current therapies by stimulating reparative processes in sites of injury. In this context, a number of molecular options could be envisaged, alone or in combination, based on the application of regenerative (differentiated or progenitor) cells, candidate genes, and biomaterials adapted for each type of tissue and disease. The goal of this Special Issue is to offer an overview of the most advanced procedures that may be used as tools to improve the healing of musculoskeletal disorders in future translational approaches.

Prof. Dr. Magali Cucchiarini
Prof. Dr. Henning Madry
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cartilage repair
  • bone healing
  • meniscal lesions
  • tendons and ligament injuries
  • regenerative medicine Gene therapy
  • cell therapy
  • tissue engineering

Published Papers (15 papers)

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Research

Jump to: Review

15 pages, 4628 KiB  
Article
miR-103-3p Regulates the Proliferation and Differentiation of C2C12 Myoblasts by Targeting BTG2
by Yulin He, Peiyu Yang, Tiantian Yuan, Lin Zhang, Gongshe Yang, Jianjun Jin and Taiyong Yu
Int. J. Mol. Sci. 2023, 24(20), 15318; https://doi.org/10.3390/ijms242015318 - 18 Oct 2023
Viewed by 1520
Abstract
Skeletal muscle, a vital and intricate organ, plays a pivotal role in maintaining overall body metabolism, facilitating movement, and supporting normal daily activities. An accumulating body of evidence suggests that microRNA (miRNA) holds a crucial role in orchestrating skeletal muscle growth. Therefore, the [...] Read more.
Skeletal muscle, a vital and intricate organ, plays a pivotal role in maintaining overall body metabolism, facilitating movement, and supporting normal daily activities. An accumulating body of evidence suggests that microRNA (miRNA) holds a crucial role in orchestrating skeletal muscle growth. Therefore, the primary aim of this study was to investigate the influence of miR-103-3p on myogenesis. In our study, the overexpression of miR-103-3p was found to stimulate proliferation while suppressing differentiation in C2C12 myoblasts. Conversely, the inhibition of miR-103-3p expression yielded contrasting effects. Through bioinformatics analysis, potential binding sites of miR-103-3p with the 3’UTR region of BTG anti-proliferative factor 2 (BTG2) were predicted. Subsequently, dual luciferase assays conclusively demonstrated BTG2 as the direct target gene of miR-103-3p. Further investigation into the role of BTG2 in C2C12 myoblasts unveiled that its overexpression impeded proliferation and encouraged differentiation in these cells. Notably, co-transfection experiments showcased that the overexpression of BTG2 could counteract the effects induced by miR-103-3p. In summary, our findings elucidate that miR-103-3p promotes proliferation while inhibiting differentiation in C2C12 myoblasts by targeting BTG2. Full article
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
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14 pages, 3620 KiB  
Article
Adipose Tissue-Derived Products May Present Inflammatory Properties That Affect Chondrocytes and Synoviocytes from Patients with Knee Osteoarthritis
by Carola Cavallo, Angelo Boffa, Manuela Salerno, Giulia Merli, Brunella Grigolo and Giuseppe Filardo
Int. J. Mol. Sci. 2023, 24(15), 12401; https://doi.org/10.3390/ijms241512401 - 03 Aug 2023
Viewed by 903
Abstract
Adipose tissue-derived cell-based injectable therapies have been demonstrated to have disease-modifying effects on joint tissues in preclinical studies on animal osteoarthritis (OA) models, but clinical results are heterogeneous and not always satisfactory. The aim of this study was to investigate the influence of [...] Read more.
Adipose tissue-derived cell-based injectable therapies have been demonstrated to have disease-modifying effects on joint tissues in preclinical studies on animal osteoarthritis (OA) models, but clinical results are heterogeneous and not always satisfactory. The aim of this study was to investigate the influence of adipose tissue properties on the therapeutic effects of the adipose-derived product in an in vitro OA setting. Micro-fragmented adipose tissue (MF-AT) samples were obtained from 21 OA patients (mean age 51.7 ± 11.8 years, mean BMI 25.7 ± 4.1 kg/m2). The analysis of the MF-AT supernatant was performed to analyze the release of inflammatory factors. The effects of MF-AT inflammatory factors were investigated on chondrocytes and synoviocytes gene expression levels. Patients’ characteristics were analyzed to explore their influence on MF-AT inflammatory molecules and on the MF-AT effects on the gene expression of chondrocytes and synoviocytes. The study results demonstrated that adipose tissue-derived products may present inflammatory properties that influence the therapeutic potential for OA treatment, with products with a higher pro-inflammatory profile stimulating a higher expression of genes related to a more inflamed and catabolic phenotype. A higher pro-inflammatory cytokine pattern and a higher pro-inflammatory effect were found in adipose tissue-derived products obtained from OA patients with higher BMI. Full article
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
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16 pages, 5815 KiB  
Article
rAAV TGF-β and FGF-2 Overexpression via pNaSS-Grafted PCL Films Stimulates the Reparative Activities of Human ACL Fibroblasts
by Mahnaz Amini, Jagadeesh K. Venkatesan, Tuan N. Nguyen, Wei Liu, Amélie Leroux, Henning Madry, Véronique Migonney and Magali Cucchiarini
Int. J. Mol. Sci. 2023, 24(13), 11140; https://doi.org/10.3390/ijms241311140 - 06 Jul 2023
Cited by 1 | Viewed by 926
Abstract
Lesions in the human anterior cruciate ligament (ACL) are frequent, unsolved clinical issues due to the limited self-healing ability of the ACL and lack of treatments supporting full, durable ACL repair. Gene therapy guided through the use of biomaterials may steadily activate the [...] Read more.
Lesions in the human anterior cruciate ligament (ACL) are frequent, unsolved clinical issues due to the limited self-healing ability of the ACL and lack of treatments supporting full, durable ACL repair. Gene therapy guided through the use of biomaterials may steadily activate the processes of repair in sites of ACL injury. The goal of the present study was to test the hypothesis that functionalized poly(sodium styrene sulfonate)-grafted poly(ε-caprolactone) (pNaSS-grafted PCL) films can effectively deliver recombinant adeno-associated virus (rAAV) vectors as a means of overexpressing two reparative factors (transforming growth factor beta-TGF-β and basic fibroblast growth factor-FGF-2) in primary human ACL fibroblasts. Effective, durable rAAV reporter red fluorescent protein and candidate TGF-β and FGF-2 gene overexpression was achieved in the cells for at least 21 days, especially when pNaSS-grafted PCL films were used versus control conditions, such as ungrafted films and systems lacking vectors or films (between 1.8- and 5.2-fold differences), showing interactive regulation of growth factor production. The expression of TGF-β and FGF-2 from rAAV via PCL films safely enhanced extracellular matrix depositions of type-I/-III collagen, proteoglycans/decorin, and tenascin-C (between 1.4- and 4.5-fold differences) in the cells over time with increased levels of expression of the specific transcription factors Mohawk and scleraxis (between 1.7- and 3.7-fold differences) and without the activation of the inflammatory mediators IL-1β and TNF-α, most particularly with pNaSS-grafted PCL films relative to the controls. This work shows the value of combining rAAV gene therapy with functionalized PCL films to enhance ACL repair. Full article
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
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21 pages, 6081 KiB  
Article
Oestrogen and Vibration Improve Intervertebral Disc Cell Viability and Decrease Catabolism in Bovine Organ Cultures
by Franziska Widmayer, Cornelia Neidlinger-Wilke, Fiona Witz, Jan U. Jansen, Anita Ignatius, Melanie Haffner-Luntzer and Graciosa Q. Teixeira
Int. J. Mol. Sci. 2023, 24(7), 6143; https://doi.org/10.3390/ijms24076143 - 24 Mar 2023
Viewed by 1460
Abstract
Postmenopausal women are at an increased risk for intervertebral disc degeneration, possibly due to the decrease in oestrogen levels. Low-magnitude, high-frequency vibration (LMHFV) is applied as a therapeutic approach for postmenopausal osteoporosis; however, less is known regarding possible effects on the intervertebral disc [...] Read more.
Postmenopausal women are at an increased risk for intervertebral disc degeneration, possibly due to the decrease in oestrogen levels. Low-magnitude, high-frequency vibration (LMHFV) is applied as a therapeutic approach for postmenopausal osteoporosis; however, less is known regarding possible effects on the intervertebral disc (IVD) and whether these may be oestrogen-dependent. The present study investigated the effect of 17β-oestradiol (E2) and LMHFV in an IVD organ culture model. Bovine IVDs (n = 6 IVDs/group) were treated with either (i) E2, (ii) LMHFV or (iii) the combination of E2 + LMHFV for 2 or 14 days. Minor changes in gene expression, cellularity and matrix metabolism were observed after E2 treatment, except for a significant increase in matrix metalloproteinase (MMP)-3 and interleukin (IL)-6 production. Interestingly, LMHFV alone induced cell loss and increased IL-6 production compared to the control. The combination of E2 + LMHFV induced a protective effect against cell loss and decreased IL-6 production compared to the LMHFV group. This indicates possible benefits of oestrogen therapy for the IVDs of postmenopausal women undergoing LMHFV exercises. Full article
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
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18 pages, 4882 KiB  
Article
Hypoxia Promotes Cartilage Regeneration in Cell-Seeded 3D-Printed Bioscaffolds Cultured with a Bespoke 3D Culture Device
by Konstantinos Theodoridis, Eleni Aggelidou, Maria-Eleni Manthou and Aristeidis Kritis
Int. J. Mol. Sci. 2023, 24(7), 6040; https://doi.org/10.3390/ijms24076040 - 23 Mar 2023
Cited by 2 | Viewed by 1542
Abstract
In this study, we investigated the effect of oxygen tension on the expansion of ADMSCs and on their differentiation toward their chondrocytic phenotype, regenerating a lab-based cartilaginous tissue with superior characteristics. Controversial results with reference to MSCs that were cultured under different hypoxic [...] Read more.
In this study, we investigated the effect of oxygen tension on the expansion of ADMSCs and on their differentiation toward their chondrocytic phenotype, regenerating a lab-based cartilaginous tissue with superior characteristics. Controversial results with reference to MSCs that were cultured under different hypoxic levels, mainly in 2D culturing settings combined with or without other biochemical stimulus factors, prompted our team to study the role of hypoxia on MSCs chondrogenic differentiation within an absolute 3D environment. Specifically, we used 3D-printed honeycomb-like PCL matrices seeded with ADMSCs in the presence or absence of TGF and cultured with a prototype 3D cell culture device, which was previously shown to favor nutrient/oxygen supply, cell adhesion, and infiltration within scaffolds. These conditions resulted in high-quality hyaline cartilage that was distributed uniformly within scaffolds. The presence of the TGF medium was necessary to successfully produce cartilaginous tissues with superior molecular and increased biomechanical properties. Despite hypoxia’s beneficial effect, it was overall not enough to fully differentiate ADMSCs or even promote cell expansion within 3D scaffolds alone. Full article
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
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14 pages, 3330 KiB  
Article
Dysferlin Deficiency Results in Myofiber-Type Specific Differences in Abundances of Calcium-Handling and Glycogen Metabolism Proteins
by Erin M. Lloyd, Gavin J. Pinniger, Miranda D. Grounds and Robyn M. Murphy
Int. J. Mol. Sci. 2023, 24(1), 76; https://doi.org/10.3390/ijms24010076 - 21 Dec 2022
Cited by 1 | Viewed by 1543
Abstract
Dysferlinopathies are a clinically heterogeneous group of muscular dystrophies caused by a genetic deficiency of the membrane-associated protein dysferlin, which usually manifest post-growth in young adults. The disease is characterized by progressive skeletal muscle wasting in the limb-girdle and limbs, inflammation, accumulation of [...] Read more.
Dysferlinopathies are a clinically heterogeneous group of muscular dystrophies caused by a genetic deficiency of the membrane-associated protein dysferlin, which usually manifest post-growth in young adults. The disease is characterized by progressive skeletal muscle wasting in the limb-girdle and limbs, inflammation, accumulation of lipid droplets in slow-twitch myofibers and, in later stages, replacement of muscles by adipose tissue. Previously we reported myofiber-type specific differences in muscle contractile function of 10-month-old dysferlin-deficient BLAJ mice that could not be fully accounted for by altered myofiber-type composition. In order to further investigate these findings, we examined the impact of dysferlin deficiency on the abundance of calcium (Ca2+) handling and glucose/glycogen metabolism-related proteins in predominantly slow-twitch, oxidative soleus and fast-twitch, glycolytic extensor digitorum longus (EDL) muscles of 10-month-old wild-type (WT) C57BL/6J and dysferlin-deficient BLAJ male mice. Additionally, we compared the Ca2+ activation properties of isolated slow- and fast-twitch myofibers from 3-month-old WT and BLAJ male mice. Differences were observed for some Ca2+ handling and glucose/glycogen metabolism-related protein levels between BLAJ soleus and EDL muscles (compared with WT) that may contribute to the previously reported differences in function in these BLAJ muscles. Dysferlin deficiency did not impact glycogen content of whole muscles nor Ca2+ activation of the myofilaments, although soleus muscle from 10-month-old BLAJ mice had more glycogen than EDL muscles. These results demonstrate a further impact of dysferlin deficiency on proteins associated with excitation-contraction coupling and glycogen metabolism in skeletal muscles, potentially contributing to altered contractile function in dysferlinopathy. Full article
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
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26 pages, 6699 KiB  
Article
Dual Modification of Porous Ca-P/PLA Composites with APTES and Alendronate Improves Their Mechanical Strength and Cytobiocompatibility towards Human Osteoblasts
by Monika Biernat, Aleksandra Szwed-Georgiou, Karolina Rudnicka, Przemysław Płociński, Joanna Pagacz, Paulina Tymowicz-Grzyb, Anna Woźniak, Marcin Włodarczyk, Mateusz M. Urbaniak, Agnieszka Krupa, Paulina Rusek-Wala, Natalia Karska and Sylwia Rodziewicz-Motowidło
Int. J. Mol. Sci. 2022, 23(22), 14315; https://doi.org/10.3390/ijms232214315 - 18 Nov 2022
Cited by 7 | Viewed by 2078
Abstract
Synthetic implants are used to treat large bone defects that are often unable to regenerate, for example those caused by osteoporosis. It is necessary that the materials used to manufacture them are biocompatible and resorbable. Polymer-ceramic composites, such as those based on poly(L-lactide) [...] Read more.
Synthetic implants are used to treat large bone defects that are often unable to regenerate, for example those caused by osteoporosis. It is necessary that the materials used to manufacture them are biocompatible and resorbable. Polymer-ceramic composites, such as those based on poly(L-lactide) (PLLA) and calcium phosphate ceramics (Ca-P), are often used for these purposes. In this study, we attempted to investigate an innovative strategy for two-step (dual) modification of composites and their components to improve the compatibility of composite components and the adhesion between PLA and Ca-P whiskers, and to increase the mechanical strength of the composite, as well as improve osteological bioactivity and prevent bone resorption in composites intended for bone regeneration. In the first step, Ca-P whiskers were modified with a saturated fatty acid namely, lauric acid (LA), or a silane coupling agent γ-aminopropyltriethoxysilane (APTES). Then, the composite, characterized by the best mechanical properties, was modified in the second stage of the work with an active chemical compound used in medicine as a first-line drug in osteoporosis—sodium alendronate, belonging to the group of bisphosphonates (BP). As a result of the research covered in this work, the composite modified with APTES and alendronate was found to be a promising candidate for future biomedical engineering applications. Full article
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
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26 pages, 11063 KiB  
Article
Effects of Sterilization and Hydrolytic Degradation on the Structure, Morphology and Compressive Strength of Polylactide-Hydroxyapatite Composites
by Mirosław Kasprzak, Agnieszka Szabłowska, Agata Kurzyk, Paulina Tymowicz-Grzyb, Adrian Najmrodzki, Anna Woźniak, Agnieszka Antosik, Joanna Pagacz, Piotr Szterner, Andrzej Plichta, Piotr Wieciński, Paulina Rusek-Wala, Agnieszka Krupa, Przemysław Płociński, Karolina Rudnicka and Monika Biernat
Int. J. Mol. Sci. 2022, 23(18), 10454; https://doi.org/10.3390/ijms231810454 - 09 Sep 2022
Cited by 3 | Viewed by 1920
Abstract
Composites based on polylactide (PLA) and hydroxyapatite (HA) were prepared using a thermally induced phase separation method. In the experimental design, the PLA with low weight-average molar mass (Mw) and high Mw were tested with the inclusion of HA [...] Read more.
Composites based on polylactide (PLA) and hydroxyapatite (HA) were prepared using a thermally induced phase separation method. In the experimental design, the PLA with low weight-average molar mass (Mw) and high Mw were tested with the inclusion of HA synthesized as whiskers or hexagonal rods. In addition, the structure of HA whiskers was doped with Zn, whereas hexagonal rods were mixed with Sr salt. The composites were sterilized and then incubated in phosphate-buffered saline for 12 weeks at 37 °C, followed by characterization of pore size distribution, molecular properties, density and mechanical strength. Results showed a substantial reduction of PLA Mw for both polymers due to the preparation of composites, their sterilization and incubation. The distribution of pore size effectively increased after the degradation process, whereas the sterilization, furthermore, had an impact on pore size distribution depending on HA added. The inclusion of HA reduced to some extent the degradation of PLA quantitatively in the weight loss in vitro compared to the control without HA. All produced materials showed no cytotoxicity when validated against L929 mouse skin fibroblasts and hFOB 1.19 human osteoblasts. The lack of cytotoxicity was accompanied by the immunocompatibility with human monocytic cells that were able to detect pyrogenic contaminants. Full article
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
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Review

Jump to: Research

28 pages, 2714 KiB  
Review
Effect of Aging on Tendon Biology, Biomechanics and Implications for Treatment Approaches
by Ka Yu Carissa Kwan, Ka Wai Kerry Ng, Ying Rao, Chenxian Zhu, Shengcai Qi, Rocky S. Tuan, Dai Fei Elmer Ker and Dan Michelle Wang
Int. J. Mol. Sci. 2023, 24(20), 15183; https://doi.org/10.3390/ijms242015183 - 14 Oct 2023
Cited by 1 | Viewed by 3346
Abstract
Tendon aging is associated with an increasing prevalence of tendon injuries and/or chronic tendon diseases, such as tendinopathy, which affects approximately 25% of the adult population. Aged tendons are often characterized by a reduction in the number and functionality of tendon stem/progenitor cells [...] Read more.
Tendon aging is associated with an increasing prevalence of tendon injuries and/or chronic tendon diseases, such as tendinopathy, which affects approximately 25% of the adult population. Aged tendons are often characterized by a reduction in the number and functionality of tendon stem/progenitor cells (TSPCs), fragmented or disorganized collagen bundles, and an increased deposition of glycosaminoglycans (GAGs), leading to pain, inflammation, and impaired mobility. Although the exact pathology is unknown, overuse and microtrauma from aging are thought to be major causative factors. Due to the hypovascular and hypocellular nature of the tendon microenvironment, healing of aged tendons and related injuries is difficult using current pain/inflammation and surgical management techniques. Therefore, there is a need for novel therapies, specifically cellular therapy such as cell rejuvenation, due to the decreased regenerative capacity during aging. To augment the therapeutic strategies for treating tendon-aging-associated diseases and injuries, a comprehensive understanding of tendon aging pathology is needed. This review summarizes age-related tendon changes, including cell behaviors, extracellular matrix (ECM) composition, biomechanical properties and healing capacity. Additionally, the impact of conventional treatments (diet, exercise, and surgery) is discussed, and recent advanced strategies (cell rejuvenation) are highlighted to address aged tendon healing. This review underscores the molecular and cellular linkages between aged tendon biomechanical properties and the healing response, and provides an overview of current and novel strategies for treating aged tendons. Understanding the underlying rationale for future basic and translational studies of tendon aging is crucial to the development of advanced therapeutics for tendon regeneration. Full article
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
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35 pages, 32044 KiB  
Review
Regenerating Myofibers after an Acute Muscle Injury: What Do We Really Know about Them?
by Francis X. Pizza and Kole H. Buckley
Int. J. Mol. Sci. 2023, 24(16), 12545; https://doi.org/10.3390/ijms241612545 - 08 Aug 2023
Cited by 3 | Viewed by 2095
Abstract
Injury to skeletal muscle through trauma, physical activity, or disease initiates a process called muscle regeneration. When injured myofibers undergo necrosis, muscle regeneration gives rise to myofibers that have myonuclei in a central position, which contrasts the normal, peripheral position of myonuclei. Myofibers [...] Read more.
Injury to skeletal muscle through trauma, physical activity, or disease initiates a process called muscle regeneration. When injured myofibers undergo necrosis, muscle regeneration gives rise to myofibers that have myonuclei in a central position, which contrasts the normal, peripheral position of myonuclei. Myofibers with central myonuclei are called regenerating myofibers and are the hallmark feature of muscle regeneration. An important and underappreciated aspect of muscle regeneration is the maturation of regenerating myofibers into a normal sized myofiber with peripheral myonuclei. Strikingly, very little is known about processes that govern regenerating myofiber maturation after muscle injury. As knowledge of myofiber formation and maturation during embryonic, fetal, and postnatal development has served as a foundation for understanding muscle regeneration, this narrative review discusses similarities and differences in myofiber maturation during muscle development and regeneration. Specifically, we compare and contrast myonuclear positioning, myonuclear accretion, myofiber hypertrophy, and myofiber morphology during muscle development and regeneration. We also discuss regenerating myofibers in the context of different types of myofiber necrosis (complete and segmental) after muscle trauma and injurious contractions. The overall goal of the review is to provide a framework for identifying cellular and molecular processes of myofiber maturation that are unique to muscle regeneration. Full article
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
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20 pages, 2100 KiB  
Review
A Review on the Crosstalk between Insulin and Wnt/β-Catenin Signalling for Bone Health
by Sok Kuan Wong, Nur Vaizura Mohamad, Putri Ayu Jayusman and Nurul ‘Izzah Ibrahim
Int. J. Mol. Sci. 2023, 24(15), 12441; https://doi.org/10.3390/ijms241512441 - 04 Aug 2023
Viewed by 1295
Abstract
A positive association between insulin resistance and osteoporosis has been widely established. However, crosstalk between the signalling molecules in insulin and Wingless (Wnt)/beta-(β-)catenin transduction cascades orchestrating bone homeostasis remains not well understood. The current review aims to collate the existing evidence, reporting (a) [...] Read more.
A positive association between insulin resistance and osteoporosis has been widely established. However, crosstalk between the signalling molecules in insulin and Wingless (Wnt)/beta-(β-)catenin transduction cascades orchestrating bone homeostasis remains not well understood. The current review aims to collate the existing evidence, reporting (a) the expression of insulin signalling molecules involved in bone-related disorders and (b) the expression of Wnt/β-catenin signalling molecules involved in governing insulin homeostasis. The downstream effector molecule, glycogen synthase kinase-3 beta (GSK3β), has been identified to be a point of convergence linking the two signal transduction networks. This review highlights that GSK3β may be a drug target in the development of novel anabolic agents and the potential use of GSK3β inhibitors to treat bone-related disorders. Full article
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
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22 pages, 1252 KiB  
Review
Protein Aggregates and Aggrephagy in Myopathies
by Sara Gibertini, Alessandra Ruggieri, Marta Cheli and Lorenzo Maggi
Int. J. Mol. Sci. 2023, 24(9), 8456; https://doi.org/10.3390/ijms24098456 - 08 May 2023
Cited by 4 | Viewed by 1837
Abstract
A number of muscular disorders are hallmarked by the aggregation of misfolded proteins within muscle fibers. A specialized form of macroautophagy, termed aggrephagy, is designated to remove and degrade protein aggregates. This review aims to summarize what has been studied so far about [...] Read more.
A number of muscular disorders are hallmarked by the aggregation of misfolded proteins within muscle fibers. A specialized form of macroautophagy, termed aggrephagy, is designated to remove and degrade protein aggregates. This review aims to summarize what has been studied so far about the direct involvement of aggrephagy and the activation of the key players, among others, p62, NBR1, Alfy, Tollip, Optineurin, TAX1BP1 and CCT2 in muscular diseases. In the first part of the review, we describe the aggrephagy pathway with the involved proteins; then, we illustrate the muscular disorder histologically characterized by protein aggregates, highlighting the role of aggrephagy pathway abnormalities in these muscular disorders. Full article
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
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17 pages, 911 KiB  
Review
Mesenchymal Stem Cell-Derived Extracellular Vesicles: Hype or Hope for Skeletal Muscle Anti-Frailty
by Elancheleyen Mahindran, Wan Safwani Wan Kamarul Zaman, Khairul Bariah Ahmad Amin Noordin, Yuen-Fen Tan and Fazlina Nordin
Int. J. Mol. Sci. 2023, 24(9), 7833; https://doi.org/10.3390/ijms24097833 - 25 Apr 2023
Cited by 3 | Viewed by 1952
Abstract
Steadily rising population ageing is a global demographic trend due to the advancement of new treatments and technologies in the medical field. This trend also indicates an increasing prevalence of age-associated diseases, such as loss of muscle mass (sarcopenia), which tends to afflict [...] Read more.
Steadily rising population ageing is a global demographic trend due to the advancement of new treatments and technologies in the medical field. This trend also indicates an increasing prevalence of age-associated diseases, such as loss of muscle mass (sarcopenia), which tends to afflict the older population. The deterioration in muscle function can cause severe disability and seriously affects a patient’s quality of life. Currently, there is no treatment to prevent and reverse age-related skeletal muscle ageing frailty. Existing interventions mainly slow down and control the signs and symptoms. Mesenchymal stem cell-derived extracellular vesicle (MSC-EV) therapy is a promising approach to attenuate age-related skeletal muscle ageing frailty. However, more studies, especially large-scale randomised clinical trials need to be done in order to determine the adequacy of MSC-EV therapy in treating age-related skeletal muscle ageing frailty. This review compiles the present knowledge of the causes and changes regarding skeletal muscle ageing frailty and the potential of MSC-EV transplantation as a regenerative therapy for age-related skeletal muscle ageing frailty and its clinical trials. Full article
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
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33 pages, 1538 KiB  
Review
Advanced Gene Therapy Strategies for the Repair of ACL Injuries
by Mahnaz Amini, Jagadeesh K. Venkatesan, Wei Liu, Amélie Leroux, Tuan Ngoc Nguyen, Henning Madry, Véronique Migonney and Magali Cucchiarini
Int. J. Mol. Sci. 2022, 23(22), 14467; https://doi.org/10.3390/ijms232214467 - 21 Nov 2022
Cited by 2 | Viewed by 3059
Abstract
The anterior cruciate ligament (ACL), the principal ligament for stabilization of the knee, is highly predisposed to injury in the human population. As a result of its poor intrinsic healing capacities, surgical intervention is generally necessary to repair ACL lesions, yet the outcomes [...] Read more.
The anterior cruciate ligament (ACL), the principal ligament for stabilization of the knee, is highly predisposed to injury in the human population. As a result of its poor intrinsic healing capacities, surgical intervention is generally necessary to repair ACL lesions, yet the outcomes are never fully satisfactory in terms of long-lasting, complete, and safe repair. Gene therapy, based on the transfer of therapeutic genetic sequences via a gene vector, is a potent tool to durably and adeptly enhance the processes of ACL repair and has been reported for its workability in various experimental models relevant to ACL injuries in vitro, in situ, and in vivo. As critical hurdles to the effective and safe translation of gene therapy for clinical applications still remain, including physiological barriers and host immune responses, biomaterial-guided gene therapy inspired by drug delivery systems has been further developed to protect and improve the classical procedures of gene transfer in the future treatment of ACL injuries in patients, as critically presented here. Full article
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
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Review
Strategies to Convert Cells into Hyaline Cartilage: Magic Spells for Adult Stem Cells
by Anastasiia D. Kurenkova, Irina A. Romanova, Pavel D. Kibirskiy, Peter Timashev and Ekaterina V. Medvedeva
Int. J. Mol. Sci. 2022, 23(19), 11169; https://doi.org/10.3390/ijms231911169 - 22 Sep 2022
Cited by 7 | Viewed by 4237
Abstract
Damaged hyaline cartilage gradually decreases joint function and growing pain significantly reduces the quality of a patient’s life. The clinically approved procedure of autologous chondrocyte implantation (ACI) for treating knee cartilage lesions has several limits, including the absence of healthy articular cartilage tissues [...] Read more.
Damaged hyaline cartilage gradually decreases joint function and growing pain significantly reduces the quality of a patient’s life. The clinically approved procedure of autologous chondrocyte implantation (ACI) for treating knee cartilage lesions has several limits, including the absence of healthy articular cartilage tissues for cell isolation and difficulties related to the chondrocyte expansion in vitro. Today, various ACI modifications are being developed using autologous chondrocytes from alternative sources, such as the auricles, nose and ribs. Adult stem cells from different tissues are also of great interest due to their less traumatic material extraction and their innate abilities of active proliferation and chondrogenic differentiation. According to the different adult stem cell types and their origin, various strategies have been proposed for stem cell expansion and initiation of their chondrogenic differentiation. The current review presents the diversity in developing applied techniques based on autologous adult stem cell differentiation to hyaline cartilage tissue and targeted to articular cartilage damage therapy. Full article
(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine 4.0)
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