A Comparative Study of the Bone Regenerative Effect of Chemically Modified RNA Encoding BMP-2 or BMP-9

Khorsand, Behnoush; Elangovan, Satheesh; Hong, Liu; Dewerth, Alexander; Kormann, Michael; Salem, Aliasger K.

doi:10.1208/s12248-016-0034-8

Cited by 66 publications

(48 citation statements)

References 32 publications

(40 reference statements)

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“…BMP9, which belongs to the TGF-β superfamily, can induce MSCs, such as mouse embryonic fibroblasts (MEFs) or C3H10 cells, to differentiate into bone tissue [17,22,23,71,72]. Further, MSC-to-osteoblast transition is driven by BMP9, the most potent osteogenesis-inducing BMP signal in vitro and in vivo [21,22,73]. MSCs originating from the mesoderm can be isolated from different tissues [5,74,75,76,77].…”

Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Zhang

Xu²,

Chen³

et al. 2019

Preprint

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30Germ cell 1 spermatogonial (GC-1spg) cells are multipotent progenitor cells. We 31 previously confirmed that bone morphogenetic protein (BMP) 9 is among the most 32 osteogenic BMPs. However, whether GC-1spg cells are driven toward osteogenic 33 differentiation under proper stimuli is uncertain. Additionally, the molecular 34 mechanism of BMP9 remains unclear. In the present study, we aimed to determine 35 whether BMP9 can induce osteogenic differentiation of GC-1spg cells. Recombinant 36 adenoviruses were generated by the AdEasy system to regulate the BMP9 expression in 37 GC-1spg cells. We identified osteogenic markers by real-time PCR and staining 38 techniques in vitro. Ectopic ossification assays and histological analysis were also 39 performed to verify the in vivo activity of BMP9. Finally, potential signaling pathways 40 of BMP9 were assessed by transcriptome sequencing and KEGG enrichment analysis. 41Using recombinant adenoviruses, we demonstrate that BMP9 upregulates osteogenic 42 markers including Runx2, osteocalcin, osteopontin, and Sox9. BMP9 also activates 43 alkaline phosphatase activity and calcium deposition in GC-1spg cells. In vivo results 44show that BMP9 overexpression in GC-1spg cells promotes ectopic bone formation and 45 chondrogenesis. In addition, RNA-sequencing and KEGG pathway analysis 3 46 demonstrate that several signaling pathways are involved in BMP9-mediated 47 osteogenesis. GC-1spg cells not only maintain spermatogenesis but also retain the 48 ability to form bone tissue. Therefore, BMP9 activity in GC-1spg cells may help 49 identify signaling pathways implicated in bone formation and could be of use in 50 regenerative medicine. 51 Keywords: Bone morphogenetic protein 9, RNA-seq, KEGG pathway analysis, 52 recombinant adenovirus, chondrogenesis 53 Introduction 54 Germ cell 1 spermatogonial (GC-1spg) cells are mouse spermatogonia that are 55 immortalized by the SV40 large T antigen [1]. These cells can differentiate into diverse cell 56 types or undergo self-renewal, depending on different factors [2,3,4]. GC-1spg cells are 57 largely involved in spermatogenesis and have mesenchymal stem cell (MSC) differentiation 58 potential [5,6,7,8]. In other words, GC-1spg cells can differentiate into different cell types, 59including those of the osteogenic, chondrogenic, or adipogenic lineages [9,10,11,12]. 60However, several molecular events [13,14] and factors are involved in osteogenic 61 differentiation of MSCs. Importantly, bone morphogenetic proteins (BMPs) are essential for 62 this process [15,16,17]. 63 BMPs, members of the TGF-β superfamily, are required for bone formation, stem cell 64 differentiation, and male reproduction [15,16,18,19,20]. Thus far, more than 15 different 65 BMPs have been identified. Our previous work showed that BMP9 is the most osteogenic 66 BMP [21,22,23,24]. BMP9, also known as growth differentiation factor 2 (GDF-2)[25], was 67 originally isolated from the fetal mouse liver [25,26]. Bone formation involves BMP9 acting 68 through the Notch signaling ...

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Section: Discussionmentioning

confidence: 99%

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Zhang

Xu²,

Chen³

et al. 2019

Preprint

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“…Further to this, the use of chemically modified mRNAs encoding for various BMPs has also demonstrated the promotion of bone regeneration in vivo when delivered using a fibrin gel. Chemically modified BMP‐9 RNA demonstrated enhanced osteogenic differentiation by BMSCs in rat calvarial defect models, as evidenced by increased bone matrix production, with the connectivity of the newly formed bone greater following treatment with BMP‐9 RNA compared with the delivery of BMP‐2 RNA …”

Section: Gene‐activated Scaffolds For Orthopedic Tissue Engineeringmentioning

confidence: 99%

Scaffold‐Based Delivery of Nucleic Acid Therapeutics for Enhanced Bone and Cartilage Repair

Kelly

Raftery

Curtin

et al. 2019

Journal Orthopaedic Research

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Recent advances in tissue engineering have made progress toward the development of biomaterials capable of the delivery of growth factors, such as bone morphogenetic proteins, in order to promote enhanced tissue repair. However, controlling the release of these growth factors on demand and within the desired localized area is a significant challenge and the associated high costs and side effects of uncontrolled delivery have proven increasingly problematic in clinical orthopedics. Gene therapy may be a valuable tool to avoid the limitations of local delivery of growth factors. Following a series of setbacks in the 1990s, the field of gene therapy is now seeing improvements in safety and efficacy resulting in substantial clinical progress and a resurgence in confidence. Biomaterial scaffoldmediated gene therapy provides a template for cell infiltration and tissue formation while promoting transfection of cells to engineer therapeutic proteins in a sustained but ultimately transient fashion. Additionally, scaffold-mediated delivery of RNA-based therapeutics can silence specific genes associated with orthopedic pathological states. This review will provide an overview of the current state-of-theart in the field of gene-activated scaffolds and their use within orthopedic tissue engineering applications.

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“…The effect of BMP2 on bone regeneration was previously shown using gene or protein therapy. Recent publications demonstrated successful bone regeneration following application of cmRNAs encoding BMP2 in femur and calvarial bone defect models. Regarding cardiovascular regeneration, Hadas et al reported successful differentiation of cardiomyocytes and heart regeneration following application of VEGF cmRNA .…”

Section: Cell Programming and Tissue Engineering Using Mrnamentioning

confidence: 99%

Concise Review: Application of Chemically Modified mRNA in Cell Fate Conversion and Tissue Engineering

Badieyan

Evans

2019

Stem Cells Translational Medicine

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Chemically modified RNA (cmRNA) has potential as a safe and efficient tool for nucleic acid‐based therapies and regenerative medicine. Modifications in the chemistry of mRNA can enhance stability, reduce immunogenicity, and thus facilitate mRNA‐based nucleic acid therapy, which eliminates risk of insertional mutagenesis. In addition to these valuable advantages, the mRNA‐based method showed significantly higher efficacy for reprogramming somatic cells to pluripotency compared with DNA‐ or protein‐based methods. These findings suggest cmRNA can provide a powerful and safe tool for cell programming and reprogramming. Delivery methods, particularly using lipid nanoparticles, provide strategies for cell and organ‐specific targeting. The present study comprehensively compares studies that have used cmRNAs for cell fate conversion and tissue engineering. The information should be useful for investigators looking to choose the most efficient and straightforward cmRNA‐based strategy and protocol for tissue engineering and regenerative medicine research. Stem Cells Translational Medicine 2019;8:833&843

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A Comparative Study of the Bone Regenerative Effect of Chemically Modified RNA Encoding BMP-2 or BMP-9

Cited by 66 publications

References 32 publications

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells

Scaffold‐Based Delivery of Nucleic Acid Therapeutics for Enhanced Bone and Cartilage Repair

Concise Review: Application of Chemically Modified mRNA in Cell Fate Conversion and Tissue Engineering

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