Mesenchymal stem cells overexpressing BMP-9 by CRISPR-Cas9 present high in vitro osteogenic potential and enhance in vivo bone formation

Freitas, Gileade Pereira; Lopes, Helena Bacha; Souza, Alann Thaffarell Portilho; Gomes, Maria Paula; Quiles, Georgia K; Gordon, Jonathan A. R.; Tye, Coralee E.; Stein, Janet L.; Lian, Jane B.; Beloti, Márcio Mateus

doi:10.1038/s41434-021-00248-8

Cited by 30 publications

(43 citation statements)

References 59 publications

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“…In the second route, Wnt4 acts via Fzd2 that activates the JNK (c-Jun-N-terminal kinase) and p38 pathways. These pathways jointly stimulate the upregulation of two decisive bone morphogenetic factors, BMP9 and its most important downstream mediator [208], Runx2. Additionally, the differentiation-related transcription factor Osx (osterix) is upregulated, a process that would require further clarification.…”

Section: Melatonin Effects In the Presence Of Wnt: Chondrogenesis And...mentioning

confidence: 99%

Melatonin and the Programming of Stem Cells

Hardeland

2022

IJMS

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Melatonin interacts with various types of stem cells, in multiple ways that comprise stimulation of proliferation, maintenance of stemness and self-renewal, protection of survival, and programming toward functionally different cell lineages. These various properties are frequently intertwined but may not be always jointly present. Melatonin typically stimulates proliferation and transition to the mature cell type. For all sufficiently studied stem or progenitor cells, melatonin’s signaling pathways leading to expression of respective morphogenetic factors are discussed. The focus of this article will be laid on the aspect of programming, particularly in pluripotent cells. This is especially but not exclusively the case in neural stem cells (NSCs) and mesenchymal stem cells (MSCs). Concerning developmental bifurcations, decisions are not exclusively made by melatonin alone. In MSCs, melatonin promotes adipogenesis in a Wnt (Wingless-Integration-1)-independent mode, but chondrogenesis and osteogenesis Wnt-dependently. Melatonin upregulates Wnt, but not in the adipogenic lineage. This decision seems to depend on microenvironment and epigenetic memory. The decision for chondrogenesis instead of osteogenesis, both being Wnt-dependent, seems to involve fibroblast growth factor receptor 3. Stem cell-specific differences in melatonin and Wnt receptors, and contributions of transcription factors and noncoding RNAs are outlined, as well as possibilities and the medical importance of re-programming for transdifferentiation.

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Section: Melatonin Effects In the Presence Of Wnt: Chondrogenesis And...mentioning

confidence: 99%

Melatonin and the Programming of Stem Cells

Hardeland

2022

IJMS

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“…The delivery of transduced cells promoted mature bone formation, effectively repairing the cranial defect. Clustered regularly interspaced short palindromic repeats/associated nuclease Cas9 (CRISPR-Cas9) activation has recently been used to induce endogenous BMP-9 in immortalized mouse bone-marrow-derived MSCs transduced with lentiviral vectors [150]. Two weeks after generating a cranial defect, BMP-9 overexpressing cells were directly injected in the lesion using the newly formed connective tissue as a natural scaffold to retain the cells in the defect.…”

Section: Cell-based Gene Therapy For Cranial Bone Regenerationmentioning

confidence: 99%

A Narrative Review of Cell-Based Approaches for Cranial Bone Regeneration

et al. 2022

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Current cranial repair techniques combine the use of autologous bone grafts and biomaterials. In addition to their association with harvesting morbidity, autografts are often limited by insufficient quantity of bone stock. Biomaterials lead to better outcomes, but their effectiveness is often compromised by the unpredictable lack of integration and structural failure. Bone tissue engineering offers the promising alternative of generating constructs composed of instructive biomaterials including cells or cell-secreted products, which could enhance the outcome of reconstructive treatments. This review focuses on cell-based approaches with potential to regenerate calvarial bone defects, including human studies and preclinical research. Further, we discuss strategies to deliver extracellular matrix, conditioned media and extracellular vesicles derived from cell cultures. Recent advances in 3D printing and bioprinting techniques that appear to be promising for cranial reconstruction are also discussed. Finally, we review cell-based gene therapy approaches, covering both unregulated and regulated gene switches that can create spatiotemporal patterns of transgenic therapeutic molecules. In summary, this review provides an overview of the current developments in cell-based strategies with potential to enhance the surgical armamentarium for regenerating cranial vault defects.

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“…Promising results are emerging with the use of CRISPR technology in the field of bone regeneration. Freitas et al (2021) used CRISPR-Cas9 to overexpress BMP-9 in mesenchymal stem cells (MSCs) and when these genetically edited cells were injected into rat calvarial bone defects, the BMP-9-overexpressing MSCs were able to repair these defects, with increased bone formation and bone mineral density [158]. Hutchinson et al (2019) described an innovative methodology using CRISPR/Cas9 to generate endogenous transcriptional reporter cells for the BMP pathway, and this technique could be applied to ocular lens cells to enable future investigations of BMP transcriptional activity in lens development and pathology [159].…”

Section: Genetic Mutations In Bmpsmentioning

confidence: 99%

Insights into Bone Morphogenetic Protein—(BMP-) Signaling in Ocular Lens Biology and Pathology

Shu

Lovicu

2021

Cells

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Bone morphogenetic proteins (BMPs) are a diverse class of growth factors that belong to the transforming growth factor-beta (TGFβ) superfamily. Although originally discovered to possess osteogenic properties, BMPs have since been identified as critical regulators of many biological processes, including cell-fate determination, cell proliferation, differentiation and morphogenesis, throughout the body. In the ocular lens, BMPs are important in orchestrating fundamental developmental processes such as induction of lens morphogenesis, and specialized differentiation of its fiber cells. Moreover, BMPs have been reported to facilitate regeneration of the lens, as well as abrogate pathological processes such as TGFβ-induced epithelial-mesenchymal transition (EMT) and apoptosis. In this review, we summarize recent insights in this topic and discuss the complexities of BMP-signaling including the role of individual BMP ligands, receptors, extracellular antagonists and cross-talk between canonical and non-canonical BMP-signaling cascades in the lens. By understanding the molecular mechanisms underlying BMP activity, we can advance their potential therapeutic role in cataract prevention and lens regeneration.

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Mesenchymal stem cells overexpressing BMP-9 by CRISPR-Cas9 present high in vitro osteogenic potential and enhance in vivo bone formation

Cited by 30 publications

References 59 publications

Melatonin and the Programming of Stem Cells

Melatonin and the Programming of Stem Cells

A Narrative Review of Cell-Based Approaches for Cranial Bone Regeneration

Insights into Bone Morphogenetic Protein—(BMP-) Signaling in Ocular Lens Biology and Pathology

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