The wonders of BMP9: From mesenchymal stem cell differentiation, angiogenesis, neurogenesis, tumorigenesis, and metabolism to regenerative medicine

Mostafa, Sami; Pakvasa, Mikhail; Coalson, Elam; Zhu, Allen; Alverdy, Alex; Castillo, Héctor; Fan, Jiaming; Li, Alex; Feng, Yixiao; Wu, Di; Bishop, Elliott; Du, Scott; Spezia, Mia; Li, Alissa N.; Hagag, Ofir; Deng, Alison; Liu, Winny; Li, Mingyang; Ho, Sherwin S.W.; Athiviraham, Aravind; Lee, Michael J.; Wolf, Jennifer Moriatis; Ameer, Guillermo A.; Luu, Hue H.; Haydon, Rex C.; Strelzow, Jason; Hynes, Kelly; He, Tong‐Chuan; Reid, Russell R.

doi:10.1016/j.gendis.2019.07.003

Cited by 74 publications

(66 citation statements)

References 229 publications

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“…Therefore, our results indicated that BMP9 induces both osteogenic and angiogenic differentiation of MSCs, suggesting that BMP9 is a potential growth factor for the construction of tissue engineered bone. It is still controversial whether BMP9-induced angiogenic differentiation is earlier than trabecular bone formation [15,47]. In our in vitro tests, we found that BMP9 exhibited dual potential to induce MSCs osteogenic and angiogenic differentiation at early stage (day 3).…”

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

“…BMP9 is one of the most osteogenic BMPs that induce osteogenic differentiation of stem cells [12,13,15]. Several signaling pathways have been identified to help facilitate BMP9-induced osteogenic differentiation of MSCs [15,44]. Meanwhile, BMP9 was proved to regulate postnatal angiogenesis, which indicated the angiogenic differentiation potential of BMP9 [45,46].…”

Section: Discussionmentioning

confidence: 99%

“…Through an integrated identification of the 14 types of BMPs in inducing osteogenic differentiation of MSCs, we characterized that BMP9 was one of the most osteogenic BMPs in inducing osteogenic differentiation of MSCs [11][12][13][14]. In the past decade, underlying mechanisms in BMP9-induced osteogenic differentiation of MSCs have been explored extensively [15], including Notch signaling [16][17][18], TGF-β signaling [19], epidermal growth factor (EGF) [20], classic Wnt signaling [21][22][23], Nell 1 signaling [24], long noncoding RNA H19 (lncRNA H19) [25], insulin-like growth factors (IGFs) [26], all of which were reported to participate in BMP9-induced osteogenic differentiation. Nonetheless, increasing evidence has shown that osteogenesis can not exist effectively without angiogenesis during the processes of bone development and bone formation [27][28][29], so it is indispensable to clarify underlying mechanisms of BMP9-induced osteogenesis-angiogenesis coupling of MSCs for the construction of BMP9-based bone tissue engineering.…”

Section: Introductionmentioning

confidence: 99%

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BMP9 exhibits dual and coupled roles in inducing osteogenic and angiogenic differentiation of mesenchymal stem cells

Xiao

Wang

et al. 2020

Bioscience Reports

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Bone morphogenetic protein (BMP) 9 (BMP9) is one of most potent BMPs in inducing osteogenic differentiation of mesenchymal stem cells (MSCs). Recently, evidence has shown that osteogenesis and angiogenesis are coupled, however, it is unclear whether BMP9 induces MSC differentiation into endothelial-like cells and further promotes blood vessel formation. In the present study, we explored the potential of BMP9-induced angiogenic differentiation of MSCs, and the relationship between BMP9-induced osteogenic and angiogenic differentiation of MSCs. Osteogenic activities and angiogenic differentiation markers were analyzed at mRNA and protein levels. In vivo osteogenic and angiogenic differentiation of MSCs were tested by the ectopic bone formation model. We identified that adenoviral vectors effectively transduced in immortalized mouse embryonic fibroblasts (iMEFs) and expressed BMP9 with high efficiency. We found that BMP9 induces early and late osteogenic differentiation, and it up-regulated osteogenic marker expression in MSCs. Meanwhile, BMP9 induces angiogenic differentiation of MSCs via the expression of vascular endothelial growth factor a (VEGFa) and CD31 at both mRNA and protein levels. CD31-positive cells were also increased with the stimulation of BMP9. The ectopic bone formation tests found that BMP9-induced trabecular bone formation was coupled with the expression of blood vessel formation markers and sinusoid capillary formation. These findings suggest that BMP9 exhibits dual and coupled roles in inducing osteogenic and angiogenic differentiation of MSCs.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

BMP9 exhibits dual and coupled roles in inducing osteogenic and angiogenic differentiation of mesenchymal stem cells

Xiao

Wang

et al. 2020

Bioscience Reports

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“…Bone morphogenetic proteins (BMPs) belong to the TGF-β superfamily, and play important roles in regulating embryonic development, stem cell differentiation, and adult tissue homeostasis [5–9]. There are at least 14 types of BMPs in rodents and humans [6, 7, 10]. Through a comprehensive analysis of the 14 types of human BMPs, we have demonstrated that several osteogenic BMPs, such as BMP2, 4, 6, 7 and 9, are potent factors to drive adipogenic differentiation of mesenchymal stem cells [10–13].…”

Section: Introductionmentioning

confidence: 99%

Bone morphogenetic protein 4 (BMP4) alleviates hepatic steatosis by increasing hepatic lipid turnover and inhibiting the mTORC1 signaling axis in hepatocytes

Peng

Chen

Wang

et al. 2019

Aging

Self Cite

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Liver has numerous critical metabolic functions including lipid metabolism, which is usually dysregulated in obesity, the metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD). Increasing evidence indicates bone morphogenetic proteins (BMPs) play an important role in adipogenesis and thermogenic balance in adipogenic progenitors and adipose tissue. However, the direct impact of BMPs on hepatic steatosis and possible association with NAFLD are poorly understood. Here, we found that BMP4 was up-regulated in oleic acid-induced steatosis and during the development of high fat diet (HFD)-induced NAFLD. Exogenous BMP4 reduced lipid accumulation and up-regulated the genes involved in lipid synthesis, storage and breakdown in hepatocytes. Exogenous BMP4 inhibited hepatic steatosis, reduced serum triglyceride levels and body weight, and alleviated progression of NAFLD in vivo. Mechanistically, BMP4 overexpression in hepatocytes down-regulated most components of the mTORC1 signaling axis. Collectively, these findings strongly suggest that BMP4 may play an essential role in regulating hepatic lipid metabolism and the molecular pathogenesis of NAFLD. Manipulating BMP4 and/or mTORC1 signaling axis may lead to the development of novel therapeutics for obesity, metabolic syndrome, and NAFLD.

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BMP9‐ID1 signaling promotes EpCAM‐positive cancer stem cell properties in hepatocellular carcinoma

et al. 2021

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The malignant nature of hepatocellular carcinoma (HCC) is closely related to the presence of cancer stem cells (CSCs). Bone morphologic protein 9 (BMP9), a member of the transforming growth factor-beta (TGF-β) superfamily, was recently reported to be involved in liver diseases including cancer. We aimed to elucidate the role of BMP9 signaling in HCC-CSC properties and to assess the therapeutic effect of BMP receptor inhibitors in HCC. We have identified that high BMP9 expression in tumor tissues or serum from patients with HCC leads to poorer outcome. BMP9 promoted CSC properties in epithelial cell adhesion molecule (EpCAM)-positive HCC subtype via enhancing inhibitor of DNA-binding protein 1 (ID1) expression in vitro. Additionally, ID1 knockdown significantly repressed BMP9-promoted HCC-CSC properties by suppressing Wnt/β-catenin signaling. Interestingly, cells treated with BMP receptor inhibitors K02288 and LDN-212854 blocked HCC-CSC activation by inhibiting BMP9-ID1 signaling, in contrast to cells treated with the TGF-β receptor inhibitor galunisertib. . Treatment with LDN-212854 suppressed HCC tumor growth by repressing ID1 and EpCAM in vivo. Our study demonstrates the pivotal role of BMP9-ID1 signaling in promoting HCC-CSC properties and the therapeutic potential of BMP receptor inhibitors in treating EpCAM-positive HCC. Therefore, targetingBMP9-ID1 signaling could offer novel therapeutic options for patients with malignant HCC.

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The wonders of BMP9: From mesenchymal stem cell differentiation, angiogenesis, neurogenesis, tumorigenesis, and metabolism to regenerative medicine

Cited by 74 publications

References 229 publications

BMP9 exhibits dual and coupled roles in inducing osteogenic and angiogenic differentiation of mesenchymal stem cells

BMP9 exhibits dual and coupled roles in inducing osteogenic and angiogenic differentiation of mesenchymal stem cells

Bone morphogenetic protein 4 (BMP4) alleviates hepatic steatosis by increasing hepatic lipid turnover and inhibiting the mTORC1 signaling axis in hepatocytes

BMP9‐ID1 signaling promotes EpCAM‐positive cancer stem cell properties in hepatocellular carcinoma

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