Nuclear Export of Smads by RanBP3L Regulates Bone Morphogenetic Protein Signaling and Mesenchymal Stem Cell Differentiation

Bone morphogenetic proteins (BMPs) play vital roles in regulating stem cell maintenance and differentiation. BMPs can induce osteogenesis and inhibit myogenesis of mesenchymal stem cells. Canonical BMP signaling is stringently controlled through reversible phosphorylation and nucleocytoplasmic shuttling of Smad1, Smad5, and Smad8 (Smad1/5/8). However, how the nuclear export of Smad1/5/8 is regulated remains unclear. Here we report that the Ran-binding protein RanBP3L acts as a nuclear export factor for Smad1/5/8. RanBP3L directly recognizes dephosphorylated Smad1/5/8 and mediates their nuclear export in a Ran-dependent manner. Increased expression of RanBP3L blocks BMP-induced osteogenesis of mouse bone marrow-derived mesenchymal stem cells and promotes myogenic induction of C2C12 mouse myoblasts, whereas depletion of RanBP3L expression enhances BMP-dependent stem cell differentiation activity and transcriptional responses. In conclusion, our results demonstrate that RanBP3L, as a nuclear exporter for BMP-specific Smads, plays a critical role in terminating BMP signaling and regulating mesenchymal stem cell differentiation.

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Identification of mesenchymal stem cell differentiation state using dual-micropore microfluidic impedance flow cytometry

Analytical Methods ◽

10.1039/c6ay01377e ◽

2016 ◽

Vol 8 (41) ◽

pp. 7437-7444 ◽

Cited By ~ 13

Author(s):

Hongjun Song ◽

Jenna M. Rosano ◽

Yi Wang ◽

Charles J. Garson ◽

Balabhaskar Prabhakarpandian ◽

...

Keyword(s):

Stem Cells ◽

Flow Cytometry ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Cell Differentiation ◽

Mesenchymal Stem Cell ◽

Electrical Impedance ◽

Stem Cell Differentiation ◽

Non Invasive ◽

Mesenchymal Stem Cell Differentiation

A dual-micropore-based microfluidic electrical impedance flow cytometer for non-invasive identification of the differentiation state of mesenchymal stem cells.

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Elastin-based biomaterials and mesenchymal stem cells

Biomaterials Science ◽

10.1039/c5bm00038f ◽

2015 ◽

Vol 3 (6) ◽

pp. 800-809 ◽

Cited By ~ 23

Author(s):

Jazmin Ozsvar ◽

Suzanne M. Mithieux ◽

Richard Wang ◽

Anthony S. Weiss

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Cell Differentiation ◽

Mesenchymal Stem Cell ◽

Stem Cell Differentiation ◽

Mesenchymal Stem Cell Differentiation

Elastin-based biomaterials can direct mesenchymal stem cell differentiation.

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Dynamically tunable polymer microwells for directing mesenchymal stem cell differentiation into osteogenesis

Journal of Materials Chemistry B ◽

10.1039/c5tb01682g ◽

2015 ◽

Vol 3 (46) ◽

pp. 9011-9022 ◽

Cited By ~ 15

Author(s):

Tao Gong ◽

Liuxuan Lu ◽

Dian Liu ◽

Xian Liu ◽

Kun Zhao ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Cell Differentiation ◽

Mesenchymal Stem Cell ◽

Stem Cell Differentiation ◽

Great Capacity ◽

Cytoskeletal Structure ◽

Mesenchymal Stem Cell Differentiation

Dynamically tunable geometric microwells have great capacity to regulate the cytoskeletal structure and differentiation of mesenchymal stem cells along adipogenesis and osteogenesis pathways.

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Differentiation of mesenchymal stem cells to osteoblasts and chondrocytes: a focus on adenosine receptors

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2013.2 ◽

2013 ◽

Vol 15 ◽

Cited By ~ 29

Author(s):

Shannon H. Carroll ◽

Katya Ravid

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Cell Differentiation ◽

Cyclic Amp ◽

Mesenchymal Stem Cell ◽

Adenosine Receptors ◽

Stem Cell Differentiation ◽

Post Injury ◽

Mesenchymal Stem Cell Differentiation

Skeletogenesis, either during development, post-injury or for maintenance, is a carefully coordinated process reliant on the appropriate differentiation of mesenchymal stem cells. Some well described, as well as a new regulator of this process (adenosine receptors), are alike in that they signal via cyclic-AMP (cAMP). This review highlights the known contribution of cAMP signalling to mesenchymal stem cell differentiation to osteoblasts and to chondrocytes. Focus has been given to how these regulators influence the commitment of the osteochondroprogenitor to these separate lineages.

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Correction for Chen et al., “Nuclear Export of Smads by RanBP3L Regulates Bone Morphogenetic Protein Signaling and Mesenchymal Stem Cell Differentiation”

Molecular and Cellular Biology ◽

10.1128/mcb.00287-17 ◽

2017 ◽

Vol 37 (17) ◽

Author(s):

Fenfang Chen ◽

Xia Lin ◽

Pinglong Xu ◽

Zhengmao Zhang ◽

Yanzhen Chen ◽

...

Keyword(s):

Stem Cell ◽

Cell Differentiation ◽

Mesenchymal Stem Cell ◽

Bone Morphogenetic Protein ◽

Nuclear Export ◽

Stem Cell Differentiation ◽

Protein Signaling ◽

Bone Morphogenetic Protein Signaling ◽

Mesenchymal Stem Cell Differentiation ◽

Morphogenetic Protein

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LAA and CoCl2 Pretreated Exosomes Enhance Chondrogenic Differentiation of Mesenchymal Stem Cell

10.21203/rs.3.rs-1139714/v1 ◽

2021 ◽

Author(s):

Anggraini Barlian ◽

Rizka Musdalifah Amsar ◽

Salindri Prawitasari ◽

Christofora Hanny Wijaya ◽

Ika Dewi Ana ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Cell Differentiation ◽

Mesenchymal Stem Cell ◽

Chondrogenic Differentiation ◽

Stem Cell Differentiation ◽

Human Umbilical Cord ◽

Hypoxic Conditions ◽

Transmission Electron

Abstract BackgroundCells produce extracellular vesicles, such as exosomes and microvesicles, which are used for intracellular communication. Cell-free therapies could be enhanced by using mesenchymal stem cell-derived exosomes. Preconditioning parental cells affects the properties of their exosomes. This study aimed to investigate the role of L-ascorbic acid (LAA) and CoCl2 in the exosomes produced by human Wharton’s jelly mesenchymal stem cells (hWJ MSC) and its potential to induce chondrogenic differentiation of stem cells was also studied.. MethodThe cells were obtained from umbilical cords and characterized based on mesenchymal stem cell criteria. The cells were cultured in a serum-free medium containing LAA and CoCl2. Exosomes produced by the cells were isolated and their morphology observed with Transmission Electron Microscopy. The presence of CD 63 was confirmed using ELISA. The particle size distribution and exosome concentration were analyzed with Nanoparticle Tracking Analysis (NTA). The ability of exosomes to induce stem cell differentiation into chondrocytes was investigated using the Alcian blue assay and immunocytochemistry.ResultsStem cells were successfully isolated from the human umbilical cord. The cells can differentiate into adipocytes, chondrocytes, and osteocytes. Flowcytometry analysis showed the specific surface marker of mesenchymal stem cells. Exosomes isolated from pretreatment cells showed round-shaped morphology and confirmed the presence of CD 63. NTA analysis revealed that pretreatment of cells with LAA increases exosome yields. LAA supplementation in cell medium under hypoxic conditions induced by CoCl2 produces exosomes that can induce the chondrogeic differentiation of stem cells, confirmed by the presence of glycosaminoglycan and collagen type 2.ConclusionExosomes produced by preconditioning hWJ-MSC with LAA in hypoxic conditions have the potential to enhance human Wharton Jelly stem cell differentiation into chondrocytes.

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