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| Open AccessRegulation of tumor angiogenesis and mesenchymal–endothelial transition by p38α through TGF-β and JNK signaling
Mesenchymal cells contribute to tumor angiogenesis by regulating proliferation and migration of endothelial cells. Here, the authors show that mesenchymal stem cells also have the ability to acquire an endothelial phenotype upon TGF-β stimulation via the downstream kinase JNK, and that p38α negatively regulates this process.
- Raquel Batlle
- , Eva Andrés
- & Angel R. Nebreda
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Article
| Open AccessAdult stem cell deficits drive Slc29a3 disorders in mice
Mutations in equilibrative nucleoside transporter 3 (ENT3), encoded by SLC29A3, cause a spectrum of human genetic disorders. Here, the authors show altered haematopoietic stem cell and mesenchymal stem cell fates in ENT3-deficient mice, due to misregulation of the AMPK-mTOR-ULK axis.
- Sreenath Nair
- , Anne M. Strohecker
- & Rajgopal Govindarajan
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| Open AccessTGFβ-induced degradation of TRAF3 in mesenchymal progenitor cells causes age-related osteoporosis
Increased inflammation during ageing promotes osteoporosis by activating osteoclast function and inhibiting osteoblasts. Here, the authors show that TGFβ1 release from bone matrix during ageing induces degradation of TRAF3 in mesenchymal progenitor cells, leading to reduced osteoblast differentiation and increased osteoclast formation, and suggesting that pharmacological stabilization of TRAF3 could ameliorate age-related osteoporosis.
- Jinbo Li
- , Akram Ayoub
- & Brendan F. Boyce
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Article
| Open AccessEndothelial cell clonal expansion in the development of cerebral cavernous malformations
Cerebral cavernous malformation is a vascular disease characterized by capillary-venous cavernomas in the central nervous system. Here the authors show that cavernomas display benign tumor characteristics and originate from the clonal expansion of mutated endothelial progenitors which can attract surrounding wild-type cells, inducing their mesenchymal transition and leading to growth of the cavernoma.
- Matteo Malinverno
- , Claudio Maderna
- & Elisabetta Dejana
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| Open AccessLobular architecture of human adipose tissue defines the niche and fate of progenitor cells
In human adipose tissue (AT), adipocytes are organized into units of lobules. Here the authors identify distinct fibrous septal and stromal compartments within AT lobules that differ in composition and potential between subcutaneous and visceral regions and are disturbed in obesity and metabolic syndrome.
- D. Estève
- , N. Boulet
- & J. Galitzky
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Article
| Open AccessMesenchymal stem cell therapy induces FLT3L and CD1c+ dendritic cells in systemic lupus erythematosus patients
Promising pilot clinical trials of mesenchymal stem cells (MSCs) therapy of lupus await validation in larger, controlled trials. Here the authors show that MSCs expand CD1c+ dendritic cells in cell culture by producing FLT3L, and that in lupus patients, circulating CD1c+ dendritic cells and FLT3L are increased following MSCs therapy.
- Xinran Yuan
- , Xiaodong Qin
- & Lingyun Sun
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Article
| Open AccessMethylation and PTEN activation in dental pulp mesenchymal stem cells promotes osteogenesis and reduces oncogenesis
Mesenchymal stem cells derived from dental pulp (DP-MSCs) differ in oncogenesic and developmental potential compared to those from bone marrow. Here, the authors show that decreased DNA methylation and histone H3K9Me2 enrichment along with higher PTEN activation in DP-MSCs promotes osteogenesis and reduces oncogenesis.
- Wen-Ching Shen
- , Yung-Chih Lai
- & Shih-Chieh Hung
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Article
| Open AccessArtificial cell membrane binding thrombin constructs drive in situ fibrin hydrogel formation
The incorporation of cells into tissue engineering scaffolds can be a major challenge. Here, the authors report on anchoring thrombin to cell membranes for the in situ formation of fibrin scaffolds around the modified cells, demonstrate scaffold formation in vitro and show cell survival in vivo.
- Robert C. Deller
- , Thomas Richardson
- & Adam W. Perriman
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| Open AccessOrigin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp
The white pulp of spleen is an important immune structure dynamically modulated during development and immune responses. Here the authors define, using multi-color lineage tracing and single-cell transcriptome analysis, the subset distribution and differentiation trajectory of fibroblastic reticular cells to serve structural insights for splenic white pulps.
- Hung-Wei Cheng
- , Lucas Onder
- & Burkhard Ludewig
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Article
| Open AccessVolume expansion and TRPV4 activation regulate stem cell fate in three-dimensional microenvironments
For mesenchymal stem cells (MSCs), matrix remodeling is associated with enhanced osteogenic differentiation. Here authors find that MSCs in viscoelastic hydrogels exhibit volume expansion during cell spreading, and greater volume expansion is associated with enhanced osteogenesis.
- Hong-pyo Lee
- , Ryan Stowers
- & Ovijit Chaudhuri
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Article
| Open AccessMettl3-mediated m6A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis
mRNA modifications have been shown to regulate mammalian development and disease. Here the authors show that the m6A methyltransferase Mettl3 ensures translational efficiency of the mesenchymal stem cell lineage allocator Pth1r, promoting osteogenesis and protecting from osteoporosis.
- Yunshu Wu
- , Liang Xie
- & Quan Yuan
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Article
| Open AccessCell-specific proteome analyses of human bone marrow reveal molecular features of age-dependent functional decline
Ageing causes an inability to replace damaged tissue. Here, the authors perform proteomics analyses of human haematopoietic stem cells and other cells in the bone marrow niche at different ages and show changes in central carbon metabolism, reduced bone marrow niche function, and enhanced myeloid differentiation.
- Marco L. Hennrich
- , Natalie Romanov
- & Anthony D. Ho
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| Open AccessTet1 and Tet2 maintain mesenchymal stem cell homeostasis via demethylation of the P2rX7 promoter
Tet-mediated DNA oxidation converts 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), which is essential to regulate different biological processes. Here the authors show that Tet1 and Tet2 regulate mesenchymal stem cell and bone homeostasis through demethylation of P2rX7 promoter.
- Ruili Yang
- , Tingting Yu
- & Songtao Shi
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Article
| Open AccessHypoxia induces senescence of bone marrow mesenchymal stem cells via altered gut microbiota
Systemic chronic hypoxia is a feature of many diseases and may influence the communication between bone marrow and gut microbiota. Here, the authors show that chronic hypoxia predisposes bone marrow stem cells to premature senescence, which may be due to gut dysbiosis and gut microbiota-derived d-galactose accumulation.
- Junyue Xing
- , Yongquan Ying
- & Hao Zhang
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| Open AccessPeriosteum contains skeletal stem cells with high bone regenerative potential controlled by Periostin
The periosteum, a tissue lining the bone surface, and the bone marrow are known to contain bone-forming cells. Here the authors show that skeletal stem cells reside in the mouse periosteum, and that periosteal cells have common embryonic origins with bone marrow stromal/stem cells (BMSCs), but are better at bone repair and long-term integration than BMSCs.
- Oriane Duchamp de Lageneste
- , Anaïs Julien
- & Céline Colnot
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Article
| Open AccessInhibition of overactive TGF-β attenuates progression of heterotopic ossification in mice
Heterotopic ossification (HO) is a painful disease of unknown etiology characterized by extraskeletal bone formation after injury. Here the authors show that TGF-β is increased in HO lesions, where it promotes the early stages of HO pathology, and demonstrate that TGF-β inhibition ameliorates HO in mice.
- Xiao Wang
- , Fengfeng Li
- & Xu Cao
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| Open AccessA quiescent cell population replenishes mesenchymal stem cells to drive accelerated growth in mouse incisors
Mouse incisors constantly renew from a slow cycling population of mesenchymal stem cells. Here, the authors show that upon cutting of adult incisors, a sub-population of dental mesenchymal stem cells reactivates, allowing an increased growth rate and rapid regeneration.
- Zhengwen An
- , Maja Sabalic
- & Paul T Sharpe
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Article
| Open AccessMechanically-sensitive miRNAs bias human mesenchymal stem cell fate via mTOR signalling
Mesenchymal stem cell (MSC) fate can be mechanically regulated by substrate stiffness but this is difficult to control in a 3D hydrogel. Here the authors identify miRNAs that change expression in response to substrate stiffness and RhoA signalling and show that they can bias MSC fate in a 3D soft hydrogel.
- Jessica E. Frith
- , Gina D. Kusuma
- & Justin J. Cooper-White
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| Open AccessDesumoylase SENP6 maintains osteochondroprogenitor homeostasis by suppressing the p53 pathway
Osteochondroprogenitors are essential cells for skeletal development and homeostasis. Here the authors show that the desumoylase SENP6 suppresses p53 activity by desumoylating and stabilising TRIM28, and that SENP6 ablation leads to skeletal abnormalities, senescence in osteochondroprogenitors and chondrocytes, and premature ageing.
- Jianshuang Li
- , Di Lu
- & Tao Yang
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Article
| Open AccessProgrammed cell senescence in skeleton during late puberty
Mesenchymal stem cells are essential for bone development, but it is unclear if their activity is maintained after late puberty, when bone growth decelerates. The authors show that during late puberty in mice, these cells undergo senescence under the epigenetic control of Ezh2.
- Changjun Li
- , Yu Chai
- & Mei Wan
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Article
| Open AccessHuman mesenchymal stromal cells transplanted into mice stimulate renal tubular cells and enhance mitochondrial function
Mesenchymal stromal cells drive renal regeneration following injury. Here, the authors show that human mesenchymal stromal cells, when transplanted into mice with acute kidney injury, stimulate renal tubular cell growth and enhance mitochondrial function via SIRT3.
- Luca Perico
- , Marina Morigi
- & Ariela Benigni
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Article
| Open AccessJoint morphogenetic cells in the adult mammalian synovium
The stem cells that maintain and repair adult joint tissues in mammals, including articular cartilage, remain incompletely defined. Here the authors perform lineage tracing studies in adult mice and find an ontogenetically defined progenitor cell population that is functional in the synovial joint and distinct from previously reported mesenchymal stem cell populations.
- Anke J. Roelofs
- , Janja Zupan
- & Cosimo De Bari
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Article
| Open AccessNestin+ cells direct inflammatory cell migration in atherosclerosis
Bone marrow cells producing the intermediate filament nestin guide monocyte egress to the bloodstream in response to infection. Here, the authors show that nestin-producing stromal cells direct inflammatory cell migration in atherosclerosis, and that stromal Mcp1 is crucial in this process.
- Raquel del Toro
- , Raphael Chèvre
- & Simón Méndez-Ferrer
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Article
| Open AccessMohawk promotes the maintenance and regeneration of the outer annulus fibrosus of intervertebral discs
Homeobox protein Mohwak (Mkx) is involved in tendon and ligament development. Here the authors show that Mkx in the outer annulus fibrosus of the intervertebral disc plays a role in maintenance of the IVD, showing that stem cells overexpressing Mkx enhance therapeutic IVD regeneration in mice.
- Ryo Nakamichi
- , Yoshiaki Ito
- & Hiroshi Asahara
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Article
| Open AccessRhoA determines lineage fate of mesenchymal stem cells by modulating CTGF–VEGF complex in extracellular matrix
It is unclear what regulates the fate of mesenchymal stem cells (MSCs) in arterial repair following injury. Here, the authors show that MSC differentiation following injury is triggered by RhoA which in turn stimulates the release of connective tissue growth factor and vascular endothelial growth factor.
- Changjun Li
- , Gehua Zhen
- & Mei Wan
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Article
| Open AccessProstacyclin-producing human mesenchymal cells target H19 lncRNA to augment endogenous progenitor function in hindlimb ischaemia
Human mesenchymal stem cells (hMSC) expressing paracrine factors may enhance therapeutic benefits when transplanted. Here, the authors show that hMSCs stably expressing prostacyclin enhance host regeneration and muscle mass gain in a mouse hindlimb ischaemia model, mediated by the long noncoding RNA H19.
- Yuxiao Deng
- , Zhongwei Yang
- & Qi Liu
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Article
| Open AccessInhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration
TLR and IL-1R1 ligands are danger signals released following tissue injury and during the healing response. Here, the authors show that IL-1β signalling via IL-1R1/MyD88 inhibits the Akt/GSK-3β/β-catenin pathway in mesenchymal stem cells, which suppresses their mobilization, proliferation, and differentiation into osteoblasts, processes necessary for bone regeneration.
- Mikaël M. Martino
- , Kenta Maruyama
- & Shizuo Akira
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Article
| Open AccessSingle-cell differences in matrix gene expression do not predict matrix deposition
Regenerative tissue engineering with mesenchymal stem cells is hampered by bulk methods of assessing differentiation status and a general assumption that expression of individual markers of stem cell differentiation correlate with functional capacity. Here the authors debunk this assumption by applying single-cell techniques to disassociate aggrecan mRNA abundance and matrix deposition.
- Allison J. Cote
- , Claire M. McLeod
- & Robert L. Mauck
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| Open AccessMesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs
The physiological role of crosstalk between mesenchymal stem cells (MSC) and macrophages is unclear. Here, Phinney et al. show that MSCs transfer mitochondria to macrophages under oxidative stress, and desensitize macrophages to mitochondria by using microvesicles to repress Toll receptor signalling.
- Donald G. Phinney
- , Michelangelo Di Giuseppe
- & Luis A. Ortiz
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| Open AccessArtificial membrane-binding proteins stimulate oxygenation of stem cells during engineering of large cartilage tissue
Avoiding central cell necrosis at the centre of large engineered tissue constructs is an important issue forin vitrotissue engineering. Here, the authors demonstrate that this problem may be overcome by oxygenating human mesenchymal stem cells with artificial membrane-binding proteins.
- James P. K. Armstrong
- , Rameen Shakur
- & Anthony P. Hollander
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Pharmacological repression of PPARγ promotes osteogenesis
Central to the lineage commitment of multipotent mesenchymal stem cells is the nuclear receptor PPARγ, the master regulator of adipogenesis. Here the authors use a variety of structural approaches to rationally design PPARγ inverse agonist SR2595, and demonstrate its ability to promote osteogenesis.
- David P. Marciano
- , Dana S. Kuruvilla
- & Patrick R. Griffin
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Stiffening hydrogels to probe short- and long-term cellular responses to dynamic mechanics
Studying the effects of extracellular matrix stiffening has been impeded because mostin vitromodels are static. Here, dynamic hydrogels are developed that stiffen in the presence of cells and are used to investigate the short-term (minutes-to-hours) and long-term (days-to-weeks) cellular responses to dynamic stiffening.
- Murat Guvendiren
- & Jason A. Burdick