Wnt and BMP signaling crosstalk in regulating dental stem cells: Implications in dental tissue engineering

Zhang, Fugui; Song, Jinlin; Zhang, Hongmei; Huang, Enyi; Song, Dongzhe; Tollemar, Viktor; Wang, Jing; Wang, Jinhua; Mohammed, Maryam M; Wei, Qiang; Fan, Jiaming; Liao, Junyi; Zou, Yulong; Liu, Feng; Hu, Xin; Qu, Xiangyang; Chen, Liqun; Yu, Xinyi; Luu, Hue H.; Lee, Michael J.; He, Tong‐Chuan; Ji, Ping

doi:10.1016/j.gendis.2016.09.004

Cited by 50 publications

(34 citation statements)

References 177 publications

(260 reference statements)

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“…Bone morphogenetic protein 2 (BMP2), a member of the TGFβ/BMP superfamily, regulates multiple aspects of chondrogenesis. 9 , 10 , 11 BMP2 can induce chondrogenic differentiation of mesenchymal stem cells (MSCs), such as human bone marrow-derived stromal cells (hBMSCs), adipose-derived stem cells (ADSCs), mouse embryonic fibroblasts (MEFs). 4 , 12 , 13 , 14 , 15 , 16 , 17 During development, BMP2 promotes condensation, chondrogenic differentiation, chondrocyte proliferation, and hypertrophic differentiation.…”

Section: Introductionmentioning

confidence: 99%

“… 9 , 10 , 19 , 20 , 21 In fact, BMP2 was approved by the United States Food and Drug Administration (FDA) for promoting bone regeneration in spinal fusion and nonunion fracture healing. 10 , 11 , 22 Thus, it is conceivable that BMP2 may be used for cartilage injury repair if BMP2-induced chondrogenesis in MSCs is enhanced and/or BMP2-induced osteogenesis is inhibited.…”

Section: Introductionmentioning

confidence: 99%

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Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs)

et al. 2017

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Cartilage injuries caused by arthritis or trauma pose formidable challenges for effective clinical management due to the limited intrinsic proliferative capability of chondrocytes. Autologous stem cell-based therapies and transgene-enhanced cartilage tissue engineering may open new avenues for the treatment of cartilage injuries. Bone morphogenetic protein 2 (BMP2) induces effective chondrogenesis of mesenchymal stem cells (MSCs) and can thus be explored as a potential therapeutic agent for cartilage defect repair. However, BMP2 also induces robust endochondral ossification. Although the precise mechanisms through which BMP2 governs the divergence of chondrogenesis and osteogenesis remain to be fully understood, blocking endochondral ossification during BMP2-induced cartilage formation may have practical significance for cartilage tissue engineering. Here, we investigate the role of Sox9-donwregulated Smad7 in BMP2-induced chondrogenic differentiation of MSCs. We find that overexpression of Sox9 leads to a decrease in BMP2-induced Smad7 expression in MSCs. Sox9 inhibits BMP2-induced expression of osteopontin while enhancing the expression of chondrogenic marker Col2a1 in MSCs. Forced expression of Sox9 in MSCs promotes BMP2-induced chondrogenesis and suppresses BMP2-induced endochondral ossification. Constitutive Smad7 expression inhibits BMP2-induced chondrogenesis in stem cell implantation assay. Mouse limb explant assay reveals that Sox9 expands BMP2-stimulated chondrocyte proliferating zone while Smad7 promotes BMP2-intitated hypertrophic zone of the growth plate. Cell cycle analysis indicates that Smad7 induces significant early apoptosis in BMP2-stimulated MSCs. Taken together, our results strongly suggest that Sox9 may facilitate BMP2-induced chondrogenesis by downregulating Smad7, which can be exploited for effective cartilage tissue engineering.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs)

et al. 2017

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“…While several signaling pathways, such as Wnt, Insulin-like growth factors (IGFs), Fibroblast growth factor (FGFs) and Notch, play important roles in regulating osteogenic differentiation [ 3 , 12 – 21 ], bone morphogenetic proteins (BMPs) are considered the most potent osteoinductive factors [ 22 , 23 ]. BMPs belong to the TGF-β superfamily and play critical roles in skeletal development, bone formation and stem cell differentiation [ 3 , 22 – 24 ].…”

Section: Introductionmentioning

confidence: 99%

lncRNA H19 mediates BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) through Notch signaling

et al. 2017

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Mesenchymal stem cells (MSCs) are multipotent progenitor cells that can undergo self-renewal and differentiate into multiple lineages. Osteogenic differentiation from MSCs is a well-orchestrated process and regulated by multiple signaling pathways. We previously demonstrated that BMP9 is one of the most potent osteogenic factors. However, molecular mechanism through which BMP9 governs osteoblastic differentiation remains to be fully understood. Increasing evidence indicates noncoding RNAs (ncRNAs) may play important regulatory roles in many physiological and/or pathologic processes. In this study, we investigate the role of lncRNA H19 in BMP9-regulated osteogenic differentiation of MSCs. We demonstrated that H19 was sharply upregulated at the early stage of BMP9 stimulation of MSCs, followed by a rapid decease and gradual return to basal level. This process was correlated with BMP9-induced expression of osteogenic markers. Interestingly, either constitutive H19 expression or silencing H19 expression in MSCs significantly impaired BMP9-induced osteogenic differentiation in vitro and in vivo, which was effectively rescued by the activation of Notch signaling. Either constitutive H19 expression or silencing H19 expression led to the increased expression of a group of miRNAs that are predicted to target Notch ligands and receptors. Thus, these results indicate that lncRNA H19 functions as an important mediator of BMP9 signaling by modulating Notch signaling-targeting miRNAs. Our findings suggest that the well-coordinated biphasic expression of lncRNA H19 may be essential in BMP9-induced osteogenic differentiation of MSCs, and that dysregulated H19 expression may impair normal osteogenesis, leading to pathogenic processes, such as bone tumor development.

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“…Wnt signaling plays essential roles in the development and numerous physiological and pathological processes [7–14]. Wnts are secreted glycoproteins that require extensive post-translation modifications for their biologic activity [15].…”

Section: Introductionmentioning

confidence: 99%

Noncanonical Wnt signaling plays an important role in modulating canonical Wnt-regulated stemness, proliferation and terminal differentiation of hepatic progenitors

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The liver provides vital metabolic, exocrine and endocrine functions in the body as such pathological conditions of the liver lead to high morbidity and mortality. The liver is highly regenerative and contains facultative stem cells that become activated during injury to replicate to fully recover mass and function. Canonical Wnt/β-catenin signaling plays an important role in regulating the proliferation and differentiation of liver progenitor cells during liver regeneration. However, possible roles of noncanonical Wnts in liver development and regeneration remain undefined. We previously established a reversibly-immortalized hepatic progenitor cell line (iHPx), which retains hepatic differentiation potential. Here, we analyze the expression pattern of the essential components of both canonical and noncanonical Wnt signaling pathways at different postnatal stages of mouse liver tissues and iHPx cells. We find that noncanonical Wnt4, Wnt5a, Wnt9b, Wnt10a and Wnt10b, are highly expressed concordantly with the high levels of canonical Wnts in late stages of liver tissues. Wnt5a, Wnt9b, Wnt10a and Wnt10b are able to antagonize Wnt3a-induced β-catenin/TCF activity, reduce the stemness of iHPx cells, and promote hepatic differentiation of liver progenitors. Stem cell implantation assay demonstrates that Wnt5a, Wnt9b, Wnt10a and Wnt10b can inhibit cell proliferation and promote hepatic differentiation of the iHPx progenitor cells. Our results strongly suggest that noncanonical Wnts may play an important role in fine-tuning Wnt/β-catenin functions during liver development and liver regeneration. Thus, understanding regulatory mechanisms governing proliferation and differentiation of liver progenitor cells may hold great promise to facilitate liver regeneration and/or progenitor cell-based therapies for liver diseases.

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Wnt and BMP signaling crosstalk in regulating dental stem cells: Implications in dental tissue engineering

Cited by 50 publications

References 177 publications

Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs)

Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs)

lncRNA H19 mediates BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) through Notch signaling

Noncanonical Wnt signaling plays an important role in modulating canonical Wnt-regulated stemness, proliferation and terminal differentiation of hepatic progenitors

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