IGF-1 gene-modified muscle-derived stem cells are resistant to oxidative stress via enhanced activation of IGF-1R/PI3K/AKT signaling and secretion of VEGF

Chen, Chunjing; Xu, Ying; Song, Yanfeng

doi:10.1007/s11010-013-1855-8

Cited by 36 publications

(25 citation statements)

References 36 publications

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“…From recent studies it can be suggested that MSCs have two populations: nestin positive and nestin negative [1]. Some research suggests that the MSCs express the nestin when they are under stress [21, 22]. However, further research is warranted to characterise the two populations of the MSCs and trace their origins.…”

Section: Discussionmentioning

confidence: 99%

IGF-1 enhances cell proliferation and survival during early differentiation of mesenchymal stem cells to neural progenitor-like cells

et al. 2014

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BackgroundThere has been increasing interest recently in the plasticity of mesenchymal stem cells (MSCs) and their potential to differentiate into neural lineages. To unravel the roles and effects of different growth factors in the differentiation of MSCs into neural lineages, we have differentiated MSCs into neural lineages using different combinations of growth factors. Based on previous studies of the roles of insulin-like growth factor 1 (IGF-1) in neural stem cell isolation in the laboratory, we hypothesized that IGF-1 can enhance proliferation and reduce apoptosis in neural progenitor-like cells (NPCs) during differentiation of MSCs into NCPs.We induced MSCs differentiation under four different combinations of growth factors: (A) EGF + bFGF, (B) EGF + bFGF + IGF-1, (C) EGF + bFGF + LIF, (D) EGF + bFGF + BDNF, and (E) without growth factors, as a negative control. The neurospheres formed were characterized by immunofluorescence staining against nestin, and the expression was measured by flow cytometry. Cell proliferation and apoptosis were also studied by MTS and Annexin V assay, respectively, at three different time intervals (24 hr, 3 days, and 5 days). The neurospheres formed in the four groups were then terminally differentiated into neuron and glial cells.ResultsThe four derived NPCs showed a significantly higher expression of nestin than was shown by the negative control. Among the groups treated with growth factors, NPCs treated with IGF-1 showed the highest expression of nestin. Furthermore, NPCs derived using IGF-1 exhibited the highest cell proliferation and cell survival among the treated groups. The NPCs derived from IGF-1 treatment also resulted in a better yield after the terminal differentiation into neurons and glial cells than that of the other treated groups.ConclusionsOur results suggested that IGF-1 has a crucial role in the differentiation of MSCs into neuronal lineage by enhancing the proliferation and reducing the apoptosis in the NPCs. This information will be beneficial in the long run for improving both cell-based and cell-free therapy for neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

IGF-1 enhances cell proliferation and survival during early differentiation of mesenchymal stem cells to neural progenitor-like cells

et al. 2014

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“…16 In addition, treatment with OSI-906, an inhibitor of IGF-1R, is synergistic with BTZ and resensitizes BTZ-resistant cells to BTZ treatment. 16 Of note, IGF-1R signaling has been linked to attenuation of oxidative stress in muscle cells 48 ; however, subsequent studies will be needed to determine whether inhibiting IGF-1R in MM cells affects TIGAR and ROS. In the present work, BTZ-resistant MM cells were shown to be as sensitive to targeting MUC1-C as their drug-naïve counterparts.…”

Section: Discussionmentioning

confidence: 99%

Targeting MUC1-C is synergistic with bortezomib in downregulating TIGAR and inducing ROS-mediated myeloma cell death

Kufe

Avigan

et al. 2014

Blood

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• Targeting the MUC1-C oncoprotein in MM cells potentiates BTZ-induced downregulation of TIGAR and thereby ROS-mediated death.• Targeting MUC1-C is effective in resensitizing BTZ-resistant MM cells to BTZ and thus represents a potential strategy for combination treatment.The proteosome inhibitor bortezomib (BTZ) induces endoplasmic reticulum and oxidative stress in multiple myeloma (MM) cells. The mucin 1 C-terminal subunit (MUC1-C) oncoprotein is aberrantly expressed in most MM cells, and targeting MUC1-C with GO-203, a cell-penetrating peptide inhibitor of MUC1-C homodimerization, is effective in inducing reactive oxygen species (ROS)-mediated MM cell death. The present results demonstrate that GO-203 and BTZ synergistically downregulate expression of the p53-inducible regulator of glycolysis and apoptosis (TIGAR), which promotes shunting of glucose-6-phosphate into the pentose phosphate pathway to generate reduced glutathione (GSH). In turn, GO-203 blocks BTZ-induced increases in GSH and results in synergistic increases in ROS and MM cell death. The results also demonstrate that GO-203 is effective against BTZ-resistant MM cells. We show that BTZ resistance is associated with BTZ-induced increases in TIGAR and GSH levels, and that GO-203 resensitizes BTZ-resistant cells to BTZ treatment by synergistically downregulating TIGAR and GSH. The GO-203/BTZ combination is thus highly effective in killing BTZ-resistant MM cells. These findings support a model in which targeting MUC1-C is synergistic with BTZ in suppressing TIGARmediated regulation of ROS levels and provide an experimental rationale for combining with BTZ in certain settings of BTZ resistance. (Blood. 2014;123(19):2997-3006) IntroductionMultiple myeloma (MM) is a clonal malignancy of plasma cells that is characterized in part by the abnormal synthesis and secretion of monoclonal immunoglobulins or light chains.1 Cellular homeostasis is dependent on the balanced regulation of protein synthesis and degradation, the latter of which is predominantly mediated by the ubiquitin-proteosome pathway.2 Bortezomib (BTZ) is a reversible inhibitor of the proteosome that is effective in inducing apoptosis of MM cells and is active in the treatment of this disease.1 BTZ has improved response rates of MM patients to induction therapy and is being used as consolidation after frontline treatment or transplantation. 1,3 However, intrinsic and acquired resistance to BTZ represent a challenge for the treatment of MM, which remains an incurable disease.1 BTZ has been shown to activate the unfolded protein response (UPR), a pathway induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) and associated with increases in reactive oxygen species (ROS). 4,5 In this way, BTZ treatment of MM cells induces expression of CCAAT/enhancer binding protein-homologous protein (CHOP; GADD153), a key transcription factor that participates in cellular responses to ER and oxidative stress. [6][7][8] The mechanistic basis for BTZ activity has also been attributed...

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“…These include cellular protective pathways of phosphoinositide 3 –kinase (PI 3-K) and protein kinase B (Akt) [56–63] as well as forkhead transcription factors, sirtuins, and the mechanistic target of rapamaycin (mTOR). For example, activation of Akt limits cell injury and prevents the detrimental effects of amyloid (Aβ) toxicity [21, 64, 65] and oxidative stress [66–69].…”

Section: Wisp1 Signalingmentioning

confidence: 99%

“…EPO utilizes Akt to block cell injury during Aβ exposure [26], promote the survival of retinal ganglion cells during N-methyl-d-aspartate (NMDA) toxicity [73], enhance the myocardial protective function of mobilized peripheral blood mononuclear cells [74], foster anti-inflammatory effects [75], protect against sepsis [76], limit renal cell injury [77], and limit cellular injury during models of oxidative stress [78–81]. Similar to EPO, other trophic factors also rely upon the PI 3-K and Akt pathways to foster cellular survival during toxic environments such as insulin-like growth factor-1 (IGF-1) [56], insulin [82], and brain derived neurotrophic factor [83]. …”

Section: Wisp1 Signalingmentioning

confidence: 99%

“…For example, trophic factors such as insulin-like growth factor-1 (IGF-1) [56], insulin [82], brain derived neurotrophic factor [83], and EPO [70, 73, 75–77, 225–228] rely upon Akt activation to protect cells against toxic cellular insults. In particular, EPO activates Akt using Wnt signaling pathways to phosphorylate FoxO proteins, promote the sequestration of these proteins by 14-3-3 in the cytoplasm, and block the transcription of FoxO proteins [19, 72, 78, 97, 229].…”

Section: Future Prospectives and Considerationsmentioning

confidence: 99%

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WISP1: Clinical Insights for a Proliferative and Restorative Member of the CCN Family

Maiese¹

2014

CNR

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As a proliferative and restorative entity, Wnt1 inducible signaling pathway protein 1 (WISP1) is emerging as a novel target for a number of therapeutic strategies that are relevant for disorders such as traumatic injury, neurodegeneration, musculoskeletal disorders, cardiovascular disease, pulmonary compromise, and control of tumor growth as well as distant metastases. WISP1, a target of the wingless pathway Wnt1, oversees cellular mechanisms that include apoptosis, autophagy, cellular migration, stem cell proliferation, angiogenesis, immune cell modulation, and tumorigenesis. The signal transduction pathways of WISP1 are broad and involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), mitogen activated protein (MAP) kinase, c-Jun N-terminal kinase (JNK), caspases, forkhead transcription factors, sirtuins, c-myc, glycogen synthase kinase -3β (GSK-3β), β-catenin, miRNAs, and the mechanistic target of rapamaycin (mTOR). Ultimately, these signal transduction pathways of WISP1 can result in varied and sometimes unpredictable outcomes especially for cell survival, tissue repair, and tumorigenesis that demand increased insight into the critical role WISP1 holds for cellular biology and clinical medicine.

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IGF-1 gene-modified muscle-derived stem cells are resistant to oxidative stress via enhanced activation of IGF-1R/PI3K/AKT signaling and secretion of VEGF

Cited by 36 publications

References 36 publications

IGF-1 enhances cell proliferation and survival during early differentiation of mesenchymal stem cells to neural progenitor-like cells

IGF-1 enhances cell proliferation and survival during early differentiation of mesenchymal stem cells to neural progenitor-like cells

Targeting MUC1-C is synergistic with bortezomib in downregulating TIGAR and inducing ROS-mediated myeloma cell death

WISP1: Clinical Insights for a Proliferative and Restorative Member of the CCN Family

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