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Different Strategies for Osteogenic Differentiation and Bone Regeneration 2021

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 January 2022) | Viewed by 14784

Special Issue Editor

Department of Biomedical, Surgical and Dental Sciences-University of Milan, Milan, Italy
Interests: mesenchymal stem cells; tissue engineering; osteogenic differentiation; epigenetic modifications in bone regeneration
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Autologous bone graft is the conventional gold standard treatment method for many bone defects. However, bone graft may not be sufficient due to the invasiveness of bone collection and/or limitations in the amount of bone collected from a donor site.

Tissue engineering with the use of mesenchymal stem cells provides an attractive alternative to bone grafting. Combining stem cells, artificial support systems (scaffolds) and biologically active molecules is a promising tool for tissue engineering and, in particular, for bone regeneration. Cell-laden tissue-engineered constructs should have the capability of maintaining proliferation and differentiation.

Mesenchymal stem cells (MSCs) are multipotent cells able to differentiate into mesodermal cell types such as adipocytes, osteocytes and chondrocytes. MSCs are isolated from different tissues including bone marrow, dental pulp, adipose tissue, amniotic fluid and umbilical cord blood.

An ideal scaffold used in tissue engineering for bone regeneration should be biodegradable, biocompatible, bioactive, osteoconductive, and osteoinductive. However, identifying factors and/or biomolecules that stimulate osteogenic differentiation, even through epigenetic modifications, is crucial for the success of bone regeneration. Recently, alternative strategies have been considered in bone regeneration including physical stimuli (i.e., low-power laser irradiation, LPLI).

The aim of this issue is to provide an overview of new studies, as well as updated classical studies. Papers related to any aspect of bone regeneration are welcome.

Prof. Dr. Francesca Paino
Guest Editor

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Keywords

  • mesenchymal stem cells
  • bone regeneration
  • osteogenic differentiation
  • biomaterials
  • biomolecules
  • low-power laser therapy
  • growth factors
  • osteogenic pathways
  • epigenetic modifications

Published Papers (6 papers)

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Research

18 pages, 2213 KiB  
Article
BMP-2 Long-Term Stimulation of Human Pre-Osteoblasts Induces Osteogenic Differentiation and Promotes Transdifferentiation and Bone Remodeling Processes
by Lena-Christin Ingwersen, Marcus Frank, Hendrik Naujokat, Klaas Loger, Rainer Bader and Anika Jonitz-Heincke
Int. J. Mol. Sci. 2022, 23(6), 3077; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063077 - 12 Mar 2022
Cited by 7 | Viewed by 2807
Abstract
Bone morphogenic protein (BMP-) 2 plays an important role in the regeneration of bone defects by promoting osteogenic differentiation. However, several animal studies have reported adverse side effects of BMP-2, including osteoclast activation, induction of peroxisome proliferator- activated receptor gamma (PPARG)expression, and inflammation. [...] Read more.
Bone morphogenic protein (BMP-) 2 plays an important role in the regeneration of bone defects by promoting osteogenic differentiation. However, several animal studies have reported adverse side effects of BMP-2, including osteoclast activation, induction of peroxisome proliferator- activated receptor gamma (PPARG)expression, and inflammation. High BMP-2 concentrations are thought to be responsible for these side effects. For this reason, primary pre-osteoblasts were exposed to lower BMP-2 concentrations (1 and 2 µg/mL). Long-term exposure (up to 28 days) was performed to investigate whether this stimulation protocol may promote osteogenic differentiation without causing the side effects mentioned above. The results showed that BMP-2 treatment for 14 or 28 days resulted in increased osteogenesis, through an increase in runt-related transcription factor 2, osterix, alkaline phosphatase, and integrin-binding sialoprotein expression. However, an increase in tumor necrosis factor alpha and receptor activator of nuclear factor kappa-Β ligand protein levels was observed after BMP-2 exposure, indicating also an increased potential for osteoclast activation by osteoblasts. Additionally, morphological changes like intracellular, filled vacuoles could be detected. Enhanced PPARG and perilipin 1 mRNA transcripts and lipid droplets indicated an induced adipogenic differentiation. Overall, the data demonstrate that long-term BMP-2 exposure promotes not only osteogenic differentiation but also adipogenesis and regulates mediators involved in osteoclast activation in vitro. Full article
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21 pages, 4409 KiB  
Article
Osteogenic Differentiation of Human Adipose-Derived Stem Cells Seeded on a Biomimetic Spongiosa-like Scaffold: Bone Morphogenetic Protein-2 Delivery by Overexpressing Fascia
by Bin Ren, Oliver B. Betz, Daniel Seitz, Christian Thirion, Michael Salomon, Volkmar Jansson, Peter E. Müller and Volker M. Betz
Int. J. Mol. Sci. 2022, 23(5), 2712; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23052712 - 28 Feb 2022
Cited by 2 | Viewed by 1746
Abstract
Human adipose-derived stem cells (hADSCs) have the capacity for osteogenic differentiation and, in combination with suitable biomaterials and growth factors, the regeneration of bone defects. In order to differentiate hADSCs into the osteogenic lineage, bone morphogenetic proteins (BMPs) have been proven to be [...] Read more.
Human adipose-derived stem cells (hADSCs) have the capacity for osteogenic differentiation and, in combination with suitable biomaterials and growth factors, the regeneration of bone defects. In order to differentiate hADSCs into the osteogenic lineage, bone morphogenetic proteins (BMPs) have been proven to be highly effective, especially when expressed locally by route of gene transfer, providing a constant stimulus over an extended period of time. However, the creation of genetically modified hADSCs is laborious and time-consuming, which hinders clinical translation of the approach. Instead, expedited single-surgery gene therapy strategies must be developed. Therefore, in an in vitro experiment, we evaluated a novel growth factor delivery system, comprising adenoviral BMP-2 transduced fascia tissue in terms of BMP-2 release kinetics and osteogenic effects, on hADSCs seeded on an innovative biomimetic spongiosa-like scaffold. As compared to direct BMP-2 transduction of hADSCs or addition of recombinant BMP-2, overexpressing fascia provided a more uniform, constant level of BMP-2 over 30 days. Despite considerably higher BMP-2 peak levels in the comparison groups, delivery by overexpressing fascia led to a strong osteogenic response of hADSCs. The use of BMP-2 transduced fascia in combination with hADSCs may evolve into an expedited single-surgery gene transfer approach to bone repair. Full article
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13 pages, 1332 KiB  
Article
Embedded Human Periodontal Ligament Stem Cells Spheroids Enhance Cementogenic Differentiation via Plasminogen Activator Inhibitor 1
by Madoka Yasunaga, Hiroyuki Ishikawa, Sachio Tamaoki, Hidefumi Maeda and Jun Ohno
Int. J. Mol. Sci. 2022, 23(4), 2340; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042340 - 20 Feb 2022
Viewed by 1525
Abstract
Spheroids reproduce the tissue structure that is found in vivo more accurately than classic two-dimensional (2D) monolayer cultures. We cultured human periodontal ligament stem cells (HPLSCs) as spheroids that were embedded in collagen gel to examine whether their cementogenic differentiation could be enhanced [...] Read more.
Spheroids reproduce the tissue structure that is found in vivo more accurately than classic two-dimensional (2D) monolayer cultures. We cultured human periodontal ligament stem cells (HPLSCs) as spheroids that were embedded in collagen gel to examine whether their cementogenic differentiation could be enhanced by treatment with recombinant human plasminogen activator inhibitor-1 (rhPAI-1). The upregulated expression of cementum protein 1 (CEMP1) and cementum attachment protein (CAP), established cementoblast markers, was observed in the 2D monolayer HPLSCs that were treated with rhPAI-1 for 3 weeks compared with that in the control and osteogenic-induction medium groups. In the embedded HPLSC spheroids, rhPAI-1 treatment induced interplay between the spheroids and collagenous extracellular matrix (ECM), indicating that disaggregated HPLSCs migrated and spread into the surrounding ECM 72 h after three-dimensional (3D) culture. Western blot and immunocytochemistry analyses showed that the CEMP1 expression levels were significantly upregulated in the rhPAI-1-treated embedded HPLSC spheroids compared with all the 2D monolayer HPLSCs groups and the 3D spheroid groups. Therefore, 3D collagen-embedded spheroid culture in combination with rhPAI-1 treatment may be useful for facilitating cementogenic differentiation of HPLSCs. Full article
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22 pages, 3986 KiB  
Article
Controlled Release of Epigenetically-Enhanced Extracellular Vesicles from a GelMA/Nanoclay Composite Hydrogel to Promote Bone Repair
by Kenny Man, Inês A. Barroso, Mathieu Y. Brunet, Ben Peacock, Angelica S. Federici, David A. Hoey and Sophie C. Cox
Int. J. Mol. Sci. 2022, 23(2), 832; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020832 - 13 Jan 2022
Cited by 33 | Viewed by 4942
Abstract
Extracellular vesicles (EVs) have garnered growing attention as promising acellular tools for bone repair. Although EVs’ potential for bone regeneration has been shown, issues associated with their therapeutic potency and short half-life in vivo hinders their clinical utility. Epigenetic reprogramming with the histone [...] Read more.
Extracellular vesicles (EVs) have garnered growing attention as promising acellular tools for bone repair. Although EVs’ potential for bone regeneration has been shown, issues associated with their therapeutic potency and short half-life in vivo hinders their clinical utility. Epigenetic reprogramming with the histone deacetylase inhibitor Trichostatin A (TSA) has been reported to promote the osteoinductive potency of osteoblast-derived EVs. Gelatin methacryloyl (GelMA) hydrogels functionalised with the synthetic nanoclay laponite (LAP) have been shown to effectively bind, stabilise, and improve the retention of bioactive factors. This study investigated the potential of utilising a GelMA-LAP hydrogel to improve local retention and control delivery of epigenetically enhanced osteoblast-derived EVs as a novel bone repair strategy. LAP was found to elicit a dose-dependent increase in GelMA compressive modulus and shear-thinning properties. Incorporation of the nanoclay was also found to enhance shape fidelity when 3D printed compared to LAP-free gels. Interestingly, GelMA hydrogels containing LAP displayed increased mineralisation capacity (1.41-fold) (p ≤ 0.01) over 14 days. EV release kinetics from these nanocomposite systems were also strongly influenced by LAP concentration with significantly more vesicles being released from GelMA constructs as detected by a CD63 ELISA (p ≤ 0.001). EVs derived from TSA-treated osteoblasts (TSA-EVs) enhanced proliferation (1.09-fold), migration (1.83-fold), histone acetylation (1.32-fold) and mineralisation (1.87-fold) of human bone marrow stromal cells (hBMSCs) when released from the GelMA-LAP hydrogel compared to the untreated EV gels (p ≤ 0.01). Importantly, the TSA-EV functionalised GelMA-LAP hydrogel significantly promoted encapsulated hBMSCs extracellular matrix collagen production (≥1.3-fold) and mineralisation (≥1.78-fold) in a dose-dependent manner compared to untreated EV constructs (p ≤ 0.001). Taken together, these findings demonstrate the potential of combining epigenetically enhanced osteoblast-derived EVs with a nanocomposite photocurable hydrogel to promote the therapeutic efficacy of acellular vesicle approaches for bone regeneration. Full article
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13 pages, 15359 KiB  
Article
Comparison of Bone Regeneration in Different Forms of Bovine Bone Scaffolds with Recombinant Human Bone Morphogenetic Protein-2
by Hyun Seok, Hee-Youl Kim, Dong-Cheol Kang, Jung-Ho Park and Jong Hoon Park
Int. J. Mol. Sci. 2021, 22(20), 11121; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011121 - 15 Oct 2021
Cited by 4 | Viewed by 1258
Abstract
The aim of this study was to compare the bone regeneration ability of particle and block bones, acting as bone scaffolds, with recombinant human bone morphogenetic protein (rhBMP)-2 and evaluate them as rhBMP-2 carriers. Demineralized bovine bone particles, blocks, and rhBMP-2 were grafted [...] Read more.
The aim of this study was to compare the bone regeneration ability of particle and block bones, acting as bone scaffolds, with recombinant human bone morphogenetic protein (rhBMP)-2 and evaluate them as rhBMP-2 carriers. Demineralized bovine bone particles, blocks, and rhBMP-2 were grafted into the subperiosteal space of a rat calvarial bone, and the rats were randomly divided into four groups: particle, block, P (particle)+BMP, and B (block)+BMP groups. The bone volume of the B+BMP group was significantly higher than that of the other groups (p < 0.00), with no significant difference in bone mineral density. The average adipose tissue volume of the B+BMP group was higher than that of the P+BMP group, although the difference was not significant. Adipose tissue formation was observed in the rhBMP-2 application group. Histologically, the particle and B+BMP groups showed higher formation of a new bone. However, adipose tissue and void spaces were also formed, especially in the B+BMP group. Hence, despite the formation of a large central void space, rhBMP-2 could be effectively used with block bone scaffolds and showed excellent new bone formation. Further studies are required to evaluate the changes in adipose tissue. Full article
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18 pages, 31820 KiB  
Article
Effect of N-Vinyl-2-Pyrrolidone (NVP), a Bromodomain-Binding Small Chemical, on Osteoblast and Osteoclast Differentiation and Its Potential Application for Bone Regeneration
by Viviane A. Klemmer, Nupur Khera, Barbara M. Siegenthaler, Indranil Bhattacharya, Franz E. Weber and Chafik Ghayor
Int. J. Mol. Sci. 2021, 22(20), 11052; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011052 - 13 Oct 2021
Cited by 5 | Viewed by 1672
Abstract
The human skeleton is a dynamic and remarkably organized organ system that provides mechanical support and performs a variety of additional functions. Bone tissue undergoes constant remodeling; an essential process to adapt architecture/resistance to growth and mechanical needs, but also to repair fractures [...] Read more.
The human skeleton is a dynamic and remarkably organized organ system that provides mechanical support and performs a variety of additional functions. Bone tissue undergoes constant remodeling; an essential process to adapt architecture/resistance to growth and mechanical needs, but also to repair fractures and micro-damages. Despite bone’s ability to heal spontaneously, certain situations require an additional stimulation of bone regeneration, such as non-union fractures or after tumor resection. Among the growth factors used to increase bone regeneration, bone morphogenetic protein-2 (BMP2) is certainly the best described and studied. If clinically used in high quantities, BMP2 is associated with various adverse events, including fibrosis, overshooting bone formation, induction of inflammation and swelling. In previous studies, we have shown that it was possible to reduce BMP2 doses significantly, by increasing the response and sensitivity to it with small molecules called “BMP2 enhancers”. In the present study, we investigated the effect of N-Vinyl-2-pyrrolidone (NVP) on osteoblast and osteoclast differentiation in vitro and guided bone regeneration in vivo. We showed that NVP increases BMP2-induced osteoblast differentiation and decreases RANKL-induced osteoclast differentiation in a dose-dependent manner. Moreover, in a rabbit calvarial defect model, the histomorphometric analysis revealed that bony bridging and bony regenerated area achieved with NVP-loaded poly (lactic-co-glycolic acid (PLGA) membranes were significantly higher compared to unloaded membranes. Taken together, our results suggest that NVP sensitizes BMP2-dependent pathways, enhances BMP2 effect, and inhibits osteoclast differentiation. Thus, NVP could prove useful as “osteopromotive substance” in situations where a high rate of bone regeneration is required, and in the management of bone diseases associated with excessive bone resorption, like osteoporosis. Full article
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