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Cellular Mechanisms of Bone Regeneration
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Cellular Mechanisms of Bone Regeneration

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: closed (20 February 2022) | Viewed by 55074

Special Issue Editors

Prof. Dr. Björn Behr

E-Mail Website
Guest Editor
Department of Plastic Surgery, University Hospital Bergmannsheil Bochum, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany
Interests: regenerative medicine; bone and muscle regeneration; reconstructive surgery.
Prof. Levkau Bodo

E-Mail Website
Guest Editor
Department for Molecular Medicine III, University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany
Interests: sphingolipids; osteogenesis; bone growth; lineage commitment; sphingosine-1-phosphate

Special Issue Information

Dear Colleagues,

In daily clinical practice, there are a number of diseases and injuries in which osseous regeneration is restricted and thus acts as a therapeutic point of attack. In this regard, various therapeutic approaches, such as stem cell and protein application, activation and inhibition of osteogenesis-inducing genes, and modulation of the immune system, enable us to modify the opposing processes of osteogenesis and osteoclastogenesis. Multiple studies have shown that a balance of the contrary but simultaneous processes of bone formation and degradation is the basis for adequate bone regeneration. In this regard, there are various signaling pathways at the cellular level, some of which communicate with one another, in which a large number of different transcription factors, proteins, and receptors are involved. These complex processes modulate osseous regeneration and thus bone formation.

Preclinical and clinical studies show that the modification of the intra- and intercellular processes can lead to an influence on the signaling pathways and thus has the potential to improve bone regeneration. This, in turn, may lead to progress in the therapy for the abovementioned diseases and injuries.

Topics of interest to this Special Issue include (but are not limited to):

  • molecular mechanisms of osteoblast differentiation;
  • breakdown of signaling pathways involved in osteogenesis;
  • intracellular regulatory mechanisms of osteogenesis;
  • stem-cell-related modulation of osteogenic processes; and
  • target cellular structures for osteogenic therapy approaches.

Prof. Dr. Björn Behr
Prof. Levkau Bodo
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • bone regeneration
  • osteogenesis
  • osteoblastogenesis
  • osteoblast differentiation
  • osteoklastogenesis
  • signaling pathways
  • cellular mechanisms
  • mesenchymal stem cells
  • therapeutics

Published Papers (16 papers)

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Research

Jump to: Review

24 pages, 7263 KiB  
Article
Batch Effects during Human Bone Marrow Stromal Cell Propagation Prevail Donor Variation and Culture Duration: Impact on Genotype, Phenotype and Function
by Gabriele Brachtl, Rodolphe Poupardin, Sarah Hochmann, Anna Raninger, Karsten Jürchott, Mathias Streitz, Stephan Schlickeiser, Michaela Oeller, Martin Wolf, Katharina Schallmoser, Hans-Dieter Volk, Sven Geissler and Dirk Strunk
Cells 2022, 11(6), 946; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11060946 - 10 Mar 2022
Cited by 10 | Viewed by 2620
Abstract
Donor variation is a prominent critical issue limiting the applicability of cell-based therapies. We hypothesized that batch effects during propagation of bone marrow stromal cells (BMSCs) in human platelet lysate (hPL), replacing fetal bovine serum (FBS), can affect phenotypic and functional variability. We [...] Read more.
Donor variation is a prominent critical issue limiting the applicability of cell-based therapies. We hypothesized that batch effects during propagation of bone marrow stromal cells (BMSCs) in human platelet lysate (hPL), replacing fetal bovine serum (FBS), can affect phenotypic and functional variability. We therefore investigated the impact of donor variation, hPL- vs. FBS-driven propagation and exhaustive proliferation, on BMSC epigenome, transcriptome, phenotype, coagulation risk and osteochondral regenerative function. Notably, propagation in hPL significantly increased BMSC proliferation, created significantly different gene expression trajectories and distinct surface marker signatures, already after just one passage. We confirmed significantly declining proliferative potential in FBS-expanded BMSC after proliferative challenge. Flow cytometry verified the canonical fibroblastic phenotype in culture-expanded BMSCs. We observed limited effects on DNA methylation, preferentially in FBS-driven cultures, irrespective of culture duration. The clotting risk increased over culture time. Moreover, expansion in xenogenic serum resulted in significant loss of function during 3D cartilage disk formation and significantly increased clotting risk. Superior chondrogenic function under hPL-conditions was maintained over culture. The platelet blood group and isoagglutinins had minor impact on BMSC function. These data demonstrate pronounced batch effects on BMSC transcriptome, phenotype and function due to serum factors, partly outcompeting donor variation after just one culture passage. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
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19 pages, 10137 KiB  
Article
Human Sex Matters: Y-Linked Lysine Demethylase 5D Drives Accelerated Male Craniofacial Osteogenic Differentiation
by Madlen Merten, Johannes F. W. Greiner, Tarek Niemann, Meike Grosse Venhaus, Daniel Kronenberg, Richard Stange, Dirk Wähnert, Christian Kaltschmidt, Thomas Vordemvenne and Barbara Kaltschmidt
Cells 2022, 11(5), 823; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11050823 - 26 Feb 2022
Cited by 4 | Viewed by 2152
Abstract
Female sex is increasingly associated with a loss of bone mass during aging and an increased risk of developing nonunion fractures. Hormonal factors and cell-intrinsic mechanisms are suggested to drive these sexual dimorphisms, although underlying molecular mechanisms are still a matter of debate. [...] Read more.
Female sex is increasingly associated with a loss of bone mass during aging and an increased risk of developing nonunion fractures. Hormonal factors and cell-intrinsic mechanisms are suggested to drive these sexual dimorphisms, although underlying molecular mechanisms are still a matter of debate. Here, we observed a decreased capacity of calvarial bone recovery in female rats and a profound sexually dimorphic osteogenic differentiation in human adult neural crest-derived stem cells (NCSCs). Next to an elevated expression of pro-osteogenic regulators, global transcriptomics revealed Lysine Demethylase 5D (KDM5D) to be highly upregulated in differentiating male NCSCs. Loss of function by siRNA or pharmacological inhibition of KDM5D significantly reduced the osteogenic differentiation capacity of male NCSCs. In summary, we demonstrated craniofacial osteogenic differentiation to be sexually dimorphic with the expression of KDM5D as a prerequisite for accelerated male osteogenic differentiation, emphasizing the analysis of sex-specific differences as a crucial parameter for treating bone defects. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
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12 pages, 4813 KiB  
Article
Role of Autonomous Neuropathy in Diabetic Bone Regeneration
by Johannes Maximilian Wagner, Christoph Wallner, Mustafa Becerikli, Felix Reinkemeier, Maxi von Glinski, Alexander Sogorski, Julika Huber, Stephanie Dittfeld, Kathrin Becker, Marcus Lehnhardt, Mehran Dadras and Björn Behr
Cells 2022, 11(4), 612; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11040612 - 10 Feb 2022
Cited by 5 | Viewed by 1772
Abstract
Diabetes mellitus has multiple negative effects on regenerative processes, especially on wound and fracture healing. Despite the well-known negative effects of diabetes on the autonomous nervous system, only little is known about the role in bone regeneration within this context. Subsequently, we investigated [...] Read more.
Diabetes mellitus has multiple negative effects on regenerative processes, especially on wound and fracture healing. Despite the well-known negative effects of diabetes on the autonomous nervous system, only little is known about the role in bone regeneration within this context. Subsequently, we investigated diabetic bone regeneration in db−/db− mice with a special emphasis on the sympathetic nervous system of the bone in a monocortical tibia defect model. Moreover, the effect of pharmacological sympathectomy via administration of 6-OHDA was evaluated in C57Bl6 wildtype mice. Diabetic animals as well as wildtype mice received a treatment of BRL37344, a β3-adrenergic agonist. Bones of animals were examined via µCT, aniline-blue and Masson–Goldner staining for new bone formation, TRAP staining for bone turnover and immunoflourescence staining against tyrosinhydroxylase and stromal cell-derived factor 1 (SDF-1). Sympathectomized wildtype mice showed a significantly decreased bone regeneration, just comparable to db−/db− mice. New bone formation of BRL37344 treated db−/db− and sympathectomized wildtype mice was markedly improved in histology and µCT. Immunoflourescence stainings revealed significantly increased SDF-1 due to BRL37344 treatment in diabetic animals and sympathectomized wildtypes. This study depicts the important role of the sympathetic nervous system for bone regenerative processes using the clinical example of diabetes mellitus type 2. In order to improve and gain further insights into diabetic fracture healing, β3-agonist BRL37344 proved to be a potent treatment option, restoring impaired diabetic bone regeneration. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
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15 pages, 3380 KiB  
Article
Decreased Trabecular Bone Mass in Col22a1-Deficient Mice
by Wenbo Zhao, Philip Wiedemann, Eva Maria Wölfel, Mona Neven, Stephanie Peters, Thomas Imhof, Manuel Koch, Björn Busse, Michael Amling, Thorsten Schinke and Timur Alexander Yorgan
Cells 2021, 10(11), 3020; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10113020 - 04 Nov 2021
Cited by 4 | Viewed by 2715
Abstract
The bone matrix is constantly remodeled by the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts. Whereas type I collagen is the most abundant bone matrix protein, there are several other proteins present, some of them specifically produced by osteoblasts. In a genome-wide [...] Read more.
The bone matrix is constantly remodeled by the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts. Whereas type I collagen is the most abundant bone matrix protein, there are several other proteins present, some of them specifically produced by osteoblasts. In a genome-wide expression screening for osteoblast differentiation markers we have previously identified two collagen-encoding genes with unknown function in bone remodeling. Here we show that one of them, Col22a1, is predominantly expressed in bone, cultured osteoblasts, but not in osteoclasts. Based on this specific expression pattern we generated a Col22a1-deficient mouse model, which was analyzed for skeletal defects by µCT, undecalcified histology and bone-specific histomorphometry. We observed that Col22a1-deficient mice display trabecular osteopenia, accompanied by significantly increased osteoclast numbers per bone surface. In contrast, cortical bone parameters, osteoblastogenesis or bone formation were unaffected by the absence of Col22a1. Likewise, primary osteoblasts from Col22a1-deficient mice did not display a cell-autonomous defect, and they did not show altered expression of Rankl or Opg, two key regulators of osteoclastogenesis. Taken together, we provide the first evidence for a physiological function of Col22a1 in bone remodeling, although the molecular mechanisms explaining the indirect influence of Col22a1 deficiency on osteoclasts remain to be identified. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
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20 pages, 3676 KiB  
Article
L-Plastin Phosphorylation: Possible Regulation by a TNFR1 Signaling Cascade in Osteoclasts
by Meenakshi A. Chellaiah
Cells 2021, 10(9), 2432; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092432 - 15 Sep 2021
Cited by 4 | Viewed by 2436
Abstract
Tumor necrosis factor-alpha (TNF-α) signaling regulates phosphorylation of L-plastin, which is involved in forming the nascent sealing zone, a precursor zone for the matured sealing ring. This study aimed to illustrate the molecular mechanisms of L-plastin phosphorylation and the subsequent formation of the [...] Read more.
Tumor necrosis factor-alpha (TNF-α) signaling regulates phosphorylation of L-plastin, which is involved in forming the nascent sealing zone, a precursor zone for the matured sealing ring. This study aimed to illustrate the molecular mechanisms of L-plastin phosphorylation and the subsequent formation of the nascent sealing zone in osteoclasts treated with TNF-α. Here, we report that anti-TNF-receptor 1, inhibitors of signaling proteins (Src, PI3-K, Rho, and Rho-kinase), and siRNA of TRAF-6 attenuated the phosphorylation of LPL and filamentous actin content significantly in the presence of TNF-α. An inhibitor of integrin αvβ3, PKC, or PKA did not inhibit TNF-α-induced L-plastin phosphorylation. Inhibitors of Src and PI3-K and not Rho or Rho-kinase reduced tyrosine phosphorylation of TRAF-6, suggesting that Src and PI3-K regulate TRAF-6 phosphorylation, and Rho and Rho-kinase are downstream of TRAF-6 regulation. Osteoclasts expressing constitutively active or kinase-defective Src proteins were used to determine the role of Src on L-plastin phosphorylation; similarly, the effect of Rho was confirmed by transducing TAT-fused constitutively active (V14) or dominant-negative (N19) Rho proteins into osteoclasts. Pull-down analysis with glutathione S-transferase-fused SH2 and SH3 domains of Src and PI3-K demonstrated coprecipitation of L-plastin and TRAF-6 with the SH3 and SH2 domains of the PI3-K and Src proteins. However, the actual order of the interaction of proteins requires further elucidation; a comprehensive screening should corroborate the initial findings of protein interactions via the SH2/SH3 domains. Ultimately, inhibition of the interaction of proteins with SH2/SH3 could reduce L-plastin phosphorylation and affect NSZ formation and bone resorption in conditions that display osteoclast activation and bone loss. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
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14 pages, 3372 KiB  
Article
Mice Lacking the Calcitonin Receptor Do Not Display Improved Bone Healing
by Jessika Appelt, Serafeim Tsitsilonis, Ellen Otto, Denise Jahn, Paul Köhli, Anke Baranowsky, Shan Jiang, Melanie Fuchs, Christian H. Bucher, Georg N. Duda, Karl-Heinz Frosch and Johannes Keller
Cells 2021, 10(9), 2304; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092304 - 03 Sep 2021
Cited by 4 | Viewed by 1834
Abstract
Despite significant advances in surgical techniques, treatment options for impaired bone healing are still limited. Inadequate bone regeneration is not only associated with pain, prolonged immobilization and often multiple revision surgeries, but also with high socioeconomic costs, underlining the importance of a detailed [...] Read more.
Despite significant advances in surgical techniques, treatment options for impaired bone healing are still limited. Inadequate bone regeneration is not only associated with pain, prolonged immobilization and often multiple revision surgeries, but also with high socioeconomic costs, underlining the importance of a detailed understanding of the bone healing process. In this regard, we previously showed that mice lacking the calcitonin receptor (CTR) display increased bone formation mediated through the increased osteoclastic secretion of sphingosine-1-phosphate (S1P), an osteoanabolic molecule promoting osteoblast function. Although strong evidence is now available for the crucial role of osteoclast-to-osteoblast coupling in normal bone hemostasis, the relevance of this paracrine crosstalk during bone regeneration is unknown. Therefore, our study was designed to test whether increased osteoclast-to-osteoblast coupling, as observed in CTR-deficient mice, may positively affect bone repair. In a standardized femoral osteotomy model, global CTR-deficient mice displayed no alteration in radiologic callus parameters. Likewise, static histomorphometry demonstrated moderate impairment of callus microstructure and normal osseous bridging of osteotomy ends. In conclusion, bone regeneration is not accelerated in CTR-deficient mice, and contrary to its osteoanabolic action in normal bone turnover, osteoclast-to-osteoblast coupling specifically involving the CTR-S1P axis, may only be of minor relevance during bone healing. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
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21 pages, 8987 KiB  
Article
Free Transplantation of a Tissue Engineered Bone Graft into an Irradiated, Critical-Size Femoral Defect in Rats
by Ulrike Rottensteiner-Brandl, Ulf Bertram, Lara F. Lingens, Katrin Köhn, Luitpold Distel, Tobias Fey, Carolin Körner, Raymund E. Horch and Andreas Arkudas
Cells 2021, 10(9), 2256; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092256 - 31 Aug 2021
Cited by 3 | Viewed by 2357
Abstract
Healing of large bone defects remains a challenge in reconstructive surgery, especially with impaired healing potential due to severe trauma, infection or irradiation. In vivo studies are often performed in healthy animals, which might not accurately reflect the situation in clinical cases. In [...] Read more.
Healing of large bone defects remains a challenge in reconstructive surgery, especially with impaired healing potential due to severe trauma, infection or irradiation. In vivo studies are often performed in healthy animals, which might not accurately reflect the situation in clinical cases. In the present study, we successfully combined a critical-sized femoral defect model with an ionizing radiation protocol in rats. To support bone healing, tissue-engineered constructs were transferred into the defect after ectopic preossification and prevascularization. The combination of SiHA, MSCs and BMP-2 resulted in the significant ectopic formation of bone tissue, which can easily be transferred by means of our custom-made titanium chamber. Implanted osteogenic MSCs survived in vivo for a total of 18 weeks. The use of SiHA alone did not lead to bone formation after ectopic implantation. Analysis of gene expression showed early osteoblast differentiation and a hypoxic and inflammatory environment in implanted constructs. Irradiation led to impaired bone healing, decreased vascularization and lower short-term survival of implanted cells. We conclude that our model is highly valuable for the investigation of bone healing and tissue engineering in pre-damaged tissue and that healing of bone defects can be substantially supported by combining SiHA, MSCs and BMP-2. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
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10 pages, 1462 KiB  
Article
The Adipose-Derived Stem Cell and Endothelial Cell Coculture System—Role of Growth Factors?
by Dominik Steiner, Hilkea Mutschall, Sophie Winkler, Raymund E. Horch and Andreas Arkudas
Cells 2021, 10(8), 2074; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10082074 - 13 Aug 2021
Cited by 8 | Viewed by 2503
Abstract
Adequate vascularization is a fundamental prerequisite for bone regeneration, formation and tissue engineering applications. Endothelialization of scaffold materials is a promising strategy to support neovascularization and bone tissue formation. Besides oxygen and nutrition supply, the endothelial network plays an important role concerning osteogenic [...] Read more.
Adequate vascularization is a fundamental prerequisite for bone regeneration, formation and tissue engineering applications. Endothelialization of scaffold materials is a promising strategy to support neovascularization and bone tissue formation. Besides oxygen and nutrition supply, the endothelial network plays an important role concerning osteogenic differentiation of osteoprogenitor cells and consecutive bone formation. In this study we aimed to enhance the growth stimulating, proangiogenic and osteogenic features of the ADSC and HUVEC coculture system by means of VEGFA165 and BMP2 application. We were able to show that sprouting phenomena and osteogenic differentiation were enhanced in the ADSC/HUVEC coculture. Furthermore, apoptosis was unidirectionally decreased in HUVECs, but these effects were not further enhanced upon VEGFA165 or BMP2 application. In summary, the ADSC/HUVEC coculture system per se is a powerful tool for bone tissue engineering applications. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
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18 pages, 3811 KiB  
Article
Systemic Administration of PTH Supports Vascularization in Segmental Bone Defects Filled with Ceramic-Based Bone Graft Substitute
by Holger Freischmidt, Jonas Armbruster, Emma Bonner, Thorsten Guehring, Dennis Nurjadi, Maren Bechberger, Robert Sonntag, Gerhard Schmidmaier, Paul Alfred Grützner and Lars Helbig
Cells 2021, 10(8), 2058; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10082058 - 11 Aug 2021
Cited by 7 | Viewed by 2952
Abstract
Non-unions continue to present a challenge to trauma surgeons, as current treatment options are limited, duration of treatment is long, and the outcome often unsatisfactory. Additionally, standard treatment with autologous bone grafts is associated with comorbidity at the donor site. Therefore, alternatives to [...] Read more.
Non-unions continue to present a challenge to trauma surgeons, as current treatment options are limited, duration of treatment is long, and the outcome often unsatisfactory. Additionally, standard treatment with autologous bone grafts is associated with comorbidity at the donor site. Therefore, alternatives to autologous bone grafts and further therapeutic strategies to improve on the outcome and reduce cost for care providers are desirable. In this study in Sprague–Dawley rats we employed a recently established sequential defect model, which provides a platform to test new potential therapeutic strategies on non-unions while gaining mechanistic insight into their actions. The effects of a combinatorial treatment of a bone graft substitute (HACaS+G) implantation and systemic PTH administration was assessed by µ-CT, histological analysis, and bio-mechanical testing and compared to monotreatment and controls. Although neither PTH alone nor the combination of a bone graft substitute and PTH led to the formation of a stable union, our data demonstrate a clear osteoinductive and osteoconductive effect of the bone graft substitute. Additionally, PTH administration was shown to induce vascularization, both as a single adjuvant treatment and in combination with the bone graft substitute. Thus, systemic PTH administration is a potential synergistic co-treatment to bone graft substitutes. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
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17 pages, 6422 KiB  
Article
Fibrous Demineralized Bone Matrix (DBM) Improves Bone Marrow Mononuclear Cell (BMC)-Supported Bone Healing in Large Femoral Bone Defects in Rats
by René D. Verboket, Tanja Irrle, Yannic Busche, Alexander Schaible, Katrin Schröder, Jan C. Brune, Ingo Marzi, Christoph Nau and Dirk Henrich
Cells 2021, 10(5), 1249; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10051249 - 19 May 2021
Cited by 9 | Viewed by 2661
Abstract
Regeneration of large bone defects is a major objective in trauma surgery. Bone marrow mononuclear cell (BMC)-supported bone healing was shown to be efficient after immobilization on a scaffold. We hypothesized that fibrous demineralized bone matrix (DBM) in various forms with BMCs is [...] Read more.
Regeneration of large bone defects is a major objective in trauma surgery. Bone marrow mononuclear cell (BMC)-supported bone healing was shown to be efficient after immobilization on a scaffold. We hypothesized that fibrous demineralized bone matrix (DBM) in various forms with BMCs is superior to granular DBM. A total of 65 male SD rats were assigned to five treatment groups: syngenic cancellous bone (SCB), fibrous demineralized bone matrix (f-DBM), fibrous demineralized bone matrix densely packed (f-DBM 120%), DBM granules (GDBM) and DBM granules 5% calcium phosphate (GDBM5%Ca2+). BMCs from donor rats were combined with different scaffolds and placed into 5 mm femoral bone defects. After 8 weeks, bone mineral density (BMD), biomechanical stability and histology were assessed. Similar biomechanical properties of f-DBM and SCB defects were observed. Similar bone and cartilage formation was found in all groups, but a significantly bigger residual defect size was found in GDBM. High bone healing scores were found in f-DBM (25) and SCB (25). The application of DBM in fiber form combined with the application of BMCs shows promising results comparable to the gold standard, syngenic cancellous bone. Denser packing of fibers or higher amount of calcium phosphate has no positive effect. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
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Review

Jump to: Research

32 pages, 45114 KiB  
Review
Craniofacial Bone Tissue Engineering: Current Approaches and Potential Therapy
by Arbi Aghali
Cells 2021, 10(11), 2993; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10112993 - 03 Nov 2021
Cited by 33 | Viewed by 4144
Abstract
Craniofacial bone defects can result from various disorders, including congenital malformations, tumor resection, infection, severe trauma, and accidents. Successfully regenerating cranial defects is an integral step to restore craniofacial function. However, challenges managing and controlling new bone tissue formation remain. Current advances in [...] Read more.
Craniofacial bone defects can result from various disorders, including congenital malformations, tumor resection, infection, severe trauma, and accidents. Successfully regenerating cranial defects is an integral step to restore craniofacial function. However, challenges managing and controlling new bone tissue formation remain. Current advances in tissue engineering and regenerative medicine use innovative techniques to address these challenges. The use of biomaterials, stromal cells, and growth factors have demonstrated promising outcomes in vitro and in vivo. Natural and synthetic bone grafts combined with Mesenchymal Stromal Cells (MSCs) and growth factors have shown encouraging results in regenerating critical-size cranial defects. One of prevalent growth factors is Bone Morphogenetic Protein-2 (BMP-2). BMP-2 is defined as a gold standard growth factor that enhances new bone formation in vitro and in vivo. Recently, emerging evidence suggested that Megakaryocytes (MKs), induced by Thrombopoietin (TPO), show an increase in osteoblast proliferation in vitro and bone mass in vivo. Furthermore, a co-culture study shows mature MKs enhance MSC survival rate while maintaining their phenotype. Therefore, MKs can provide an insight as a potential therapy offering a safe and effective approach to regenerating critical-size cranial defects. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
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59 pages, 4027 KiB  
Review
Effects of Extracellular Osteoanabolic Agents on the Endogenous Response of Osteoblastic Cells
by Giulia Alloisio, Chiara Ciaccio, Giovanni Francesco Fasciglione, Umberto Tarantino, Stefano Marini, Massimo Coletta and Magda Gioia
Cells 2021, 10(9), 2383; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092383 - 10 Sep 2021
Cited by 6 | Viewed by 4843
Abstract
The complex multidimensional skeletal organization can adapt its structure in accordance with external contexts, demonstrating excellent self-renewal capacity. Thus, optimal extracellular environmental properties are critical for bone regeneration and inextricably linked to the mechanical and biological states of bone. It is interesting to [...] Read more.
The complex multidimensional skeletal organization can adapt its structure in accordance with external contexts, demonstrating excellent self-renewal capacity. Thus, optimal extracellular environmental properties are critical for bone regeneration and inextricably linked to the mechanical and biological states of bone. It is interesting to note that the microstructure of bone depends not only on genetic determinants (which control the bone remodeling loop through autocrine and paracrine signals) but also, more importantly, on the continuous response of cells to external mechanical cues. In particular, bone cells sense mechanical signals such as shear, tensile, loading and vibration, and once activated, they react by regulating bone anabolism. Although several specific surrounding conditions needed for osteoblast cells to specifically augment bone formation have been empirically discovered, most of the underlying biomechanical cellular processes underneath remain largely unknown. Nevertheless, exogenous stimuli of endogenous osteogenesis can be applied to promote the mineral apposition rate, bone formation, bone mass and bone strength, as well as expediting fracture repair and bone regeneration. The following review summarizes the latest studies related to the proliferation and differentiation of osteoblastic cells, enhanced by mechanical forces or supplemental signaling factors (such as trace metals, nutraceuticals, vitamins and exosomes), providing a thorough overview of the exogenous osteogenic agents which can be exploited to modulate and influence the mechanically induced anabolism of bone. Furthermore, this review aims to discuss the emerging role of extracellular stimuli in skeletal metabolism as well as their potential roles and provide new perspectives for the treatment of bone disorders. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
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16 pages, 2125 KiB  
Review
Effects of Therapy with Fibrin Glue combined with Mesenchymal Stem Cells (MSCs) on Bone Regeneration: A Systematic Review
by Adriana de Cássia Ortiz, Simone Ortiz Moura Fideles, Karina Torres Pomini, Carlos Henrique Bertoni Reis, Cleuber Rodrigo de Souza Bueno, Eliana de Souza Bastos Mazuqueli Pereira, Jéssica de Oliveira Rossi, Paulo Cezar Novais, João Paulo Galletti Pilon, Geraldo Marco Rosa Junior, Daniela Vieira Buchaim and Rogerio Leone Buchaim
Cells 2021, 10(9), 2323; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092323 - 05 Sep 2021
Cited by 25 | Viewed by 3629
Abstract
Cell therapy strategies using mesenchymal stem cells (MSCs) carried in fibrin glue have shown promising results in regenerative medicine. MSCs are crucial for tissue healing because they have angiogenic, anti-apoptotic and immunomodulatory properties, in addition to the ability to differentiate into several specialized [...] Read more.
Cell therapy strategies using mesenchymal stem cells (MSCs) carried in fibrin glue have shown promising results in regenerative medicine. MSCs are crucial for tissue healing because they have angiogenic, anti-apoptotic and immunomodulatory properties, in addition to the ability to differentiate into several specialized cell lines. Fibrin sealant or fibrin glue is a natural polymer involved in the coagulation process. Fibrin glue provides a temporary structure that favors angiogenesis, extracellular matrix deposition and cell-matrix interactions. Additionally, fibrin glue maintains the local and paracrine functions of MSCs, providing tissue regeneration through less invasive clinical procedures. Thus, the objective of this systematic review was to assess the potential of fibrin glue combined with MSCs in bone or cartilage regeneration. The bibliographic search was performed in the PubMed/MEDLINE, LILACS and Embase databases, using the descriptors (“fibrin sealant” OR “fibrin glue”) AND “stem cells” AND “bone regeneration”, considering articles published until 2021. In this case, 12 preclinical and five clinical studies were selected to compose this review, according to the eligibility criteria. In preclinical studies, fibrin glue loaded with MSCs, alone or associated with bone substitute, significantly favored bone defects regeneration compared to scaffold without cells. Similarly, fibrin glue loaded with MSCs presented considerable potential to regenerate joint cartilage injuries and multiple bone fractures, with significant improvement in clinical parameters and absence of postoperative complications. Therefore, there is clear evidence in the literature that fibrin glue loaded with MSCs, alone or combined with bone substitute, is a promising strategy for treating lesions in bone or cartilaginous tissue. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
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17 pages, 368 KiB  
Review
Vascularization Strategies in Bone Tissue Engineering
by Filip Simunovic and Günter Finkenzeller
Cells 2021, 10(7), 1749; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10071749 - 11 Jul 2021
Cited by 61 | Viewed by 6090
Abstract
Bone is a highly vascularized tissue, and its development, maturation, remodeling, and regeneration are dependent on a tight regulation of blood vessel supply. This condition also has to be taken into consideration in the context of the development of artificial tissue substitutes. In [...] Read more.
Bone is a highly vascularized tissue, and its development, maturation, remodeling, and regeneration are dependent on a tight regulation of blood vessel supply. This condition also has to be taken into consideration in the context of the development of artificial tissue substitutes. In classic tissue engineering, bone-forming cells such as primary osteoblasts or mesenchymal stem cells are introduced into suitable scaffolds and implanted in order to treat critical-size bone defects. However, such tissue substitutes are initially avascular. Because of the occurrence of hypoxic conditions, especially in larger tissue substitutes, this leads to the death of the implanted cells. Therefore, it is necessary to devise vascularization strategies aiming at fast and efficient vascularization of implanted artificial tissues. In this review article, we present and discuss the current vascularization strategies in bone tissue engineering. These are based on the use of angiogenic growth factors, the co-implantation of blood vessel forming cells, the ex vivo microfabrication of blood vessels by means of bioprinting, and surgical methods for creating surgically transferable composite tissues. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
21 pages, 2296 KiB  
Review
The Role of Adipose Stem Cells in Bone Regeneration and Bone Tissue Engineering
by Wolfgang Mende, Rebekka Götzl, Yusuke Kubo, Thomas Pufe, Tim Ruhl and Justus P. Beier
Cells 2021, 10(5), 975; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10050975 - 21 Apr 2021
Cited by 26 | Viewed by 4110
Abstract
Bone regeneration is a complex process that is influenced by tissue interactions, inflammatory responses, and progenitor cells. Diseases, lifestyle, or multiple trauma can disturb fracture healing, which might result in prolonged healing duration or even failure. The current gold standard therapy in these [...] Read more.
Bone regeneration is a complex process that is influenced by tissue interactions, inflammatory responses, and progenitor cells. Diseases, lifestyle, or multiple trauma can disturb fracture healing, which might result in prolonged healing duration or even failure. The current gold standard therapy in these cases are bone grafts. However, they are associated with several disadvantages, e.g., donor site morbidity and availability of appropriate material. Bone tissue engineering has been proposed as a promising alternative. The success of bone-tissue engineering depends on the administered cells, osteogenic differentiation, and secretome. Different stem cell types offer advantages and drawbacks in this field, while adipose-derived stem or stromal cells (ASCs) are in particular promising. They show high osteogenic potential, osteoinductive ability, and immunomodulation properties. Furthermore, they can be harvested through a noninvasive process in high numbers. ASCs can be induced into osteogenic lineage through bioactive molecules, i.e., growth factors and cytokines. Moreover, their secretome, in particular extracellular vesicles, has been linked to fracture healing. The aim of this review is a comprehensive overview of ASCs for bone regeneration and bone tissue engineering. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
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28 pages, 2000 KiB  
Review
Appendage Regeneration in Vertebrates: What Makes This Possible?
by Valentina Daponte, Przemko Tylzanowski and Antonella Forlino
Cells 2021, 10(2), 242; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10020242 - 27 Jan 2021
Cited by 22 | Viewed by 6179
Abstract
The ability to regenerate amputated or injured tissues and organs is a fascinating property shared by several invertebrates and, interestingly, some vertebrates. The mechanism of evolutionary loss of regeneration in mammals is not understood, yet from the biomedical and clinical point of view, [...] Read more.
The ability to regenerate amputated or injured tissues and organs is a fascinating property shared by several invertebrates and, interestingly, some vertebrates. The mechanism of evolutionary loss of regeneration in mammals is not understood, yet from the biomedical and clinical point of view, it would be very beneficial to be able, at least partially, to restore that capability. The current availability of new experimental tools, facilitating the comparative study of models with high regenerative ability, provides a powerful instrument to unveil what is needed for a successful regeneration. The present review provides an updated overview of multiple aspects of appendage regeneration in three vertebrates: lizard, salamander, and zebrafish. The deep investigation of this process points to common mechanisms, including the relevance of Wnt/β-catenin and FGF signaling for the restoration of a functional appendage. We discuss the formation and cellular origin of the blastema and the identification of epigenetic and cellular changes and molecular pathways shared by vertebrates capable of regeneration. Understanding the similarities, being aware of the differences of the processes, during lizard, salamander, and zebrafish regeneration can provide a useful guide for supporting effective regenerative strategies in mammals. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Bone Regeneration)
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