Postnatal epithelium and mesenchyme stem/progenitor cells in bioengineered amelogenesis and dentinogenesis

Jiang, Nan; Zhou, Jian; Chen, Mo; Schiff, Michael; Lee, Chang H.; Kong, Kimi; Embree, Mildred C.; Mao, Jeremy J.

doi:10.1016/j.biomaterials.2013.11.061

Cited by 32 publications

(33 citation statements)

References 35 publications

(41 reference statements)

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“…The epithelium was microdissected from the underlying mesenchyme from postnatal 5/6-day-old rat incisors (Figure 1A, D, respectively). The epithelium and mesenchyme stem cells were isolated per our prior methods and cultured in exosome-free media 14 and showed typically cobblestone and spindle-like morphologies (Figure 1B, E, respectively). Transmission electron microscopy revealed cell-secreted vesicles in the size range of ~100 nm by epithelium stem cells (Figure 1C) and mesenchyme stem cells (Figure 1F).…”

Section: Resultsmentioning

confidence: 99%

Exosomes Mediate Epithelium–Mesenchyme Crosstalk in Organ Development

et al. 2017

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Organ development requires complex signaling by cells in different tissues. Epithelium and mesenchyme interactions are crucial for the development of skin, hair follicles, kidney, lungs, prostate, major glands, and teeth. Despite myriad literature on cell–cell interactions and ligand–receptor binding, the roles of extracellular vesicles in epithelium–mesenchyme interactions during organogenesis are poorly understood. Here, we discovered that ~100 nm exosomes were secreted by the epithelium and mesenchyme of a developing tooth organ and diffused through the basement membrane. Exosomes were entocytosed by epithelium or mesenchyme cells with preference by reciprocal cells rather than self-uptake. Exosomes reciprocally evoked cell differentiation and matrix synthesis: epithelium exosomes induce mesenchyme cells to produce dentin sialoprotein and undergo mineralization, whereas mesenchyme exosomes induce epithelium cells to produce basement membrane components, ameloblastin and amelogenenin. Attenuated exosomal secretion by Rab27a/b knockdown or GW4869 disrupted the basement membrane and reduced enamel and dentin production in organ culture and reduced matrix synthesis and the size of the cervical loop, which harbors epithelium stem cells, in Rab27aash/ash mutant mice. We then profiled exosomal constituents including miRNAs and peptides and further crossed all epithelium exosomal miRNAs with literature-known miRNA Wnt regulators. Epithelium exosome-derived miR135a activated Wnt/β-catenin signaling and escalated mesenchymal production of dentin matrix proteins, partially reversible by Antago-miR135a attenuation. Our results suggest that exosomes may mediate epithelium–mesenchyme crosstalk in organ development, suggesting that these vesicles and/or the molecular contents they are transporting may be interventional targets for treatment of diseases or regeneration of tissues.

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Section: Resultsmentioning

confidence: 99%

Exosomes Mediate Epithelium–Mesenchyme Crosstalk in Organ Development

et al. 2017

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“…Decoding the molecular network of Lhx8 appears to be crucial for our understanding of not only tooth development, but also tooth regeneration. E14.5 dental mesenchyme cells have the ability to induce tooth morphogenesis, when combined with non-dental epithelium[19, 41–44]. Lhx8 appears to maintain dental mesenchymal cells in an undifferentiated stage via Wnt and TGFβ pathways, and thus may be crucial in retaining the induction capacity of dental mesenchyme.…”

Section: Discussionmentioning

confidence: 99%

Lhx8 mediated Wnt and TGFβ pathways in tooth development and regeneration

et al. 2015

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LIM homeobox 8 (Lhx8) is a highly conserved transcriptional factor with recently illustrated roles in cholinergic and GABAergic differentiation, and is expressed in neural crest derived craniofacial tissues during development. However, Lhx8 functions and signaling pathways are largely elusive. Here we showed that Lhx8 regulates dental mesenchyme differentiation and function via Wnt and TGFβ pathways. Lhx8 expression was restricted to dental mesenchyme from E11.5 to a peak at E14.5, and absent in dental epithelium. By reconstituting dental epithelium and mesenchyme in an E16.5 tooth organ, Lhx8 knockdown accelerated dental mesenchyme differentiation; conversely, Lhx8 overexpression attenuated dentin formation. Lhx8 overexpressed adult human dental pulp stem/progenitor cells in β-tricalcium phosphate cubes attenuated mineralized matrix production in vivo. Gene profiling revealed that postnatal dental pulp stem/progenitor cells upon Lhx8 overexpression modified several matrix related gene expression including Dspp, Cola1 and osteocalcin. Lhx8 transcriptionally activates Wnt and TGFβ pathways, and its attenuation upregulates multiple dentinogenesis genes. Together, Lhx8 regulates dentin development and regeneration by fine-turning Wnt and TGFβ signaling.

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“…rhBMP-2, -4, and -7 are capable of stimulating the differentiation of DPSCs and form the regenerative dentin [69][70][71]. When reconstituted in a collagen gel drop and stimulated by microencapsulated and control-released BMP4, BMP7 and Wnt3a, postnatal dental epithelial and mesenchymal cells can orchestrate de novo formation of enamel-and dentin-like tissues in two integrated layers in vivo [72,73].…”

Section: Effects Of Growth Factors On Dpsc Proliferation and Differenmentioning

confidence: 98%