The Cytoskeletal Protein RHAMM and ERK1/2 Activity Maintain the Pluripotency of Murine Embryonic Stem Cells

Jiang, Jihong; Mohan, Pooja; Maxwell, Christopher A.

doi:10.1371/journal.pone.0073548

Cited by 21 publications

(19 citation statements)

References 37 publications

(51 reference statements)

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“…The phosphorylation levels of Erk1/2 and Akt were increased by CM treatment. Previous studies suggested that Erk1/2 serves as a key component in regulating the pluripotency of embryonic stem cells (Li et al, 2010;Jiang et al, 2013). In the present study, we showed that suppressing Erk1/2 decreases VEcadherin expression but rescues PPARγ expression.…”

Section: Discussionsupporting

confidence: 71%

Macrophages Contribute to the Progression of Infantile Hemangioma by Regulating the Proliferation and Differentiation of Hemangioma Stem Cells

Zhang

Chen

Wang

et al. 2015

Journal of Investigative Dermatology

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Macrophage infiltration has been implicated in infantile hemangioma (IH), the most common tumor of infancy. However, the exact role of macrophages in IH remains unknown. This study aims to clarify the functional significance of macrophages in the progression of IH. The distribution of macrophages in human IH was analyzed, and our results revealed that polarized macrophages were more prevalent in proliferating IHs than in involuting IHs, which was consistent with the increased macrophage-related cytokines in proliferating IHs. In vitro results further demonstrated that polarized macrophages effectively promoted the proliferation of hemangioma stem cells (HemSCs) and suppressed their adipogenesis in an Akt- and extracellular signal-regulated kinase 1/2 (Erk1/2)-dependent manner. Moreover, M2- but not M1-polarized macrophages promoted the endothelial differentiation of HemSCs. Furthermore, mixing macrophages in a murine hemangioma model elevated microvessel density and postponed fat tissue formation, which was concomitant with the activation of Akt and Erk1/2 signals. Cluster analysis revealed a close correlation among the macrophage markers, Ki67, vascular endothelial growth factor (VEGF), p-Akt, and p-Erk1/2 in human IH tissues. Collectively, our results suggest that macrophages in IH contribute to tumor progression by promoting the proliferation and endothelial differentiation while suppressing the adipogenesis of HemSCs. These findings indicate that targeting the infiltrating macrophages in IH is a promising therapeutic approach to accelerate IH regression.

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Section: Discussionsupporting

confidence: 71%

Macrophages Contribute to the Progression of Infantile Hemangioma by Regulating the Proliferation and Differentiation of Hemangioma Stem Cells

Zhang

Chen

Wang

et al. 2015

Journal of Investigative Dermatology

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“…However, this MAP kinase plays complex roles in adipogenesis since sustained activity blocks adipocyte maturation and promotes insulin resistance [36, 37, 69, 70]. RHAMM expression has previously been reported to be high in dormant stem cells but is down-regulated during embryonic stem cell differentiation suggesting that lowering RHAMM levels, which affect ERK1,2 activity, may be an important step in initiating differentiation of a variety of stem cells [33, 71, 72]. Our results show that RHAMM function loss is a necessary and rather specific step in directing the differentiation of mesenchymal progenitors into mature adipocytes.…”

Section: Discussionmentioning

confidence: 99%

Receptor for hyaluronan mediated motility (RHAMM/HMMR) is a novel target for promoting subcutaneous adipogenesis

et al. 2017

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Hyaluronan, CD44 and the Receptor for Hyaluronan-Mediated Motility (RHAMM, gene name HMMR) regulate stem cell differentiation including mesenchymal progenitor differentiation. Here, we show that CD44 expression is required for subcutaneous adipogenesis, whereas RHAMM expression suppresses this process. We designed RHAMM function blocking peptides to promote subcutaneous adipogenesis as a clinical and tissue engineering tool. Adipogenic RHAMM peptides were identified by screening for their ability to promote adipogenesis in culture assays using rat bone marrow mesenchymal stem cells, mouse pre-adipocyte cell lines and primary human subcutaneous pre-adipocytes. Oil red O uptake into fat droplets and adiponectin production were used as biomarkers of adipogenesis. Positive peptides were formulated in either collagen I or hyaluronan (Orthovisc) gels then assessed for their adipogenic potential in vivo following injection into dorsal rat skin and mammary fat pads. Fat content was quantified and characterized using micro CT imaging, morphometry, histology, RT-PCR and ELISA analyses of adipogenic gene expression. Injection of screened peptides increased dorsal back subcutaneous fat pad area (208.3 ± 10.4 mm2 versus control 84.11 ± 4.2 mm2; p < 0.05) and mammary fat pad size (45 ± 11 mg above control background, p=0.002) in female rats. This effect lasted >5 weeks as detected by micro CT imaging and perilipin 1 mRNA expression. RHAMM expression suppresses while blocking peptides promote expression of PPARγ, C/EBP and their target genes. Blocking RHAMM function by peptide injection or topical application is a novel and minimally invasive method for potentially promoting subcutaneous adipogenesis in lipodystrophic diseases and a complementary tool to subcutaneous fat augmentation techniques.

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“…Among the most studied receptor proteins are CD44 and receptor for hyaluronan-mediated motility (RHAMM), as they participate in inflammation and cancer motility, migration and metastasis (Slevin et al, 2007; Lokeshwar et al, 2014; Tolg et al, 2014; Misra et al, 2015). Furthermore, both CD44 and RHAMM are associated with the development of stem cell and cancer stem cell (Jiang et al, 2013; Shigeishi et al, 2013; Kouvidi et al, 2014; Jordan et al, 2015). FAK/SRC-mediated ERK activation is involved in signaling event for stem cell development.…”

Section: Ha Receptors and Signalingmentioning

confidence: 99%

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

Hsu

Chiang

Sze

et al. 2016

Front. Cell Dev. Biol.

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Hyaluronidase HYAL-2 is a membrane-anchored protein and also localizes, in part, in the lysosome. Recent study from animal models revealed that both HYAL-1 and HYAL-2 are essential for the metabolism of hyaluronan (HA). Hyal-2 deficiency is associated with chronic thrombotic microangiopathy with hemolytic anemia in mice due to over accumulation of high molecular size HA. HYAL-2 is essential for platelet generation. Membrane HYAL-2 degrades HA bound by co-receptor CD44. Also, in a non-canonical signal pathway, HYAL-2 serves as a receptor for transforming growth factor beta (TGF-β) to signal with downstream tumor suppressors WWOX and SMAD4 to control gene transcription. When SMAD4 responsive element is overly driven by the HYAL-2–WWOX–SMAD4 signaling complex, cell death occurs. When rats are subjected to traumatic brain injury, over accumulation of a HYAL-2–WWOX complex occurs in the nucleus to cause neuronal death. HA induces the signaling of HYAL-2–WWOX–SMAD4 and relocation of the signaling complex to the nucleus. If the signaling complex is overexpressed, bubbling cell death occurs in WWOX-expressing cells. In addition, a small synthetic peptide Zfra (zinc finger-like protein that regulates apoptosis) binds membrane HYAL-2 of non-T/non-B spleen HYAL-2+ CD3− CD19− Z lymphocytes and activates the cells to generate memory anticancer response against many types of cancer cells in vivo. Whether the HYAL-2–WWOX–SMAD4 signaling complex is involved is discussed. In this review and opinion article, we have updated the current knowledge of HA, HYAL-2 and WWOX, HYAL-2–WWOX–SMAD4 signaling, bubbling cell death, and Z cell activation for memory anticancer response.

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The Cytoskeletal Protein RHAMM and ERK1/2 Activity Maintain the Pluripotency of Murine Embryonic Stem Cells

Cited by 21 publications

References 37 publications

Macrophages Contribute to the Progression of Infantile Hemangioma by Regulating the Proliferation and Differentiation of Hemangioma Stem Cells

Macrophages Contribute to the Progression of Infantile Hemangioma by Regulating the Proliferation and Differentiation of Hemangioma Stem Cells

Receptor for hyaluronan mediated motility (RHAMM/HMMR) is a novel target for promoting subcutaneous adipogenesis

HYAL-2–WWOX–SMAD4 Signaling in Cell Death and Anticancer Response

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