11 research outputs found
Mechanisms of action of hESC-secreted proteins that enhance human and mouse myogenesis.
Adult stem cells grow poorly in vitro compared to embryonic stem cells, and in vivo stem cell maintenance and proliferation by tissue niches progressively deteriorates with age. We previously reported that factors produced by human embryonic stem cells (hESCs) support a robust regenerative capacity for adult and old mouse muscle stem/progenitor cells. Here we extend these findings to human muscle progenitors and investigate underlying molecular mechanisms. Our results demonstrate that hESC-conditioned medium enhanced the proliferation of mouse and human muscle progenitors. Furthermore, hESC-produced factors activated MAPK and Notch signaling in human myogenic progenitors, and Delta/Notch-1 activation was dependent on MAPK/pERK. The Wnt, TGF-β and BMP/pSmad1,5,8 pathways were unresponsive to hESC-produced factors, but BMP signaling was dependent on intact MAPK/pERK. c-Myc, p57, and p18 were key effectors of the enhanced myogenesis promoted by the hECS factors. To define some of the active ingredients of the hESC-secretome which may have therapeutic potential, a comparative proteomic antibody array analysis was performed and identified several putative proteins, including FGF2, 6 and 19 which as ligands for MAPK signaling, were investigated in more detail. These studies emphasize that a youthful signaling of multiple signaling pathways is responsible for the pro-regenerative activity of the hESC factors
hESC-secreted proteins can be enriched for multiple regenerative therapies by heparin-binding.
This work builds upon our findings that proteins secreted by hESCs exhibit pro-regenerative activity, and determines that hESC-conditioned medium robustly enhances the proliferation of both muscle and neural progenitor cells. Importantly, this work establishes that it is the proteins that bind heparin which are responsible for the pro-myogenic effects of hESC-conditioned medium, and indicates that this strategy is suitable for enriching the potentially therapeutic factors. Additionally, this work shows that hESC-secreted proteins act independently of the mitogen FGF-2, and suggests that FGF-2 is unlikely to be a pro-aging molecule in the physiological decline of old muscle repair. Moreover, hESC-secreted factors improve the viability of human cortical neurons in an Alzheimers disease (AD) model, suggesting that these factors can enhance the maintenance and regeneration of multiple tissues in the aging body
Book review: the fabric of space: water, modernity and the urban imagination
Matthew Gandy. Cambridge, MA: The MIT Press, 2014. x and 368 pp., notes, bibliography, index. 21.00 electronic (ISBN 9780-2623-2175-4)
Recommended from our members
Mechanisms of action of hESC-secreted proteins that enhance human and mouse myogenesis.
Adult stem cells grow poorly in vitro compared to embryonic stem cells, and in vivo stem cell maintenance and proliferation by tissue niches progressively deteriorates with age. We previously reported that factors produced by human embryonic stem cells (hESCs) support a robust regenerative capacity for adult and old mouse muscle stem/progenitor cells. Here we extend these findings to human muscle progenitors and investigate underlying molecular mechanisms. Our results demonstrate that hESC-conditioned medium enhanced the proliferation of mouse and human muscle progenitors. Furthermore, hESC-produced factors activated MAPK and Notch signaling in human myogenic progenitors, and Delta/Notch-1 activation was dependent on MAPK/pERK. The Wnt, TGF-β and BMP/pSmad1,5,8 pathways were unresponsive to hESC-produced factors, but BMP signaling was dependent on intact MAPK/pERK. c-Myc, p57, and p18 were key effectors of the enhanced myogenesis promoted by the hECS factors. To define some of the active ingredients of the hESC-secretome which may have therapeutic potential, a comparative proteomic antibody array analysis was performed and identified several putative proteins, including FGF2, 6 and 19 which as ligands for MAPK signaling, were investigated in more detail. These studies emphasize that a "youthful" signaling of multiple signaling pathways is responsible for the pro-regenerative activity of the hESC factors
Recommended from our members
hESC-secreted proteins can be enriched for multiple regenerative therapies by heparin-binding.
This work builds upon our findings that proteins secreted by hESCs exhibit pro-regenerative activity, and determines that hESC-conditioned medium robustly enhances the proliferation of both muscle and neural progenitor cells. Importantly, this work establishes that it is the proteins that bind heparin which are responsible for the pro-myogenic effects of hESC-conditioned medium, and indicates that this strategy is suitable for enriching the potentially therapeutic factors. Additionally, this work shows that hESC-secreted proteins act independently of the mitogen FGF-2, and suggests that FGF-2 is unlikely to be a pro-aging molecule in the physiological decline of old muscle repair. Moreover, hESC-secreted factors improve the viability of human cortical neurons in an Alzheimer's disease (AD) model, suggesting that these factors can enhance the maintenance and regeneration of multiple tissues in the aging body
Acidic pH-Targeted Chitosan-Capped Mesoporous Silica Coated Gold Nanorods Facilitate Detection of Pancreatic Tumors via Multispectral Optoacoustic Tomography
We
present a cancer nanomedicine based on acidic pH targeted gold
nanorods designed for multispectral optoacoustic tomography (MSOT).
We have designed gold nanorods coated with mesoporous silica and subsequently
capped with chitosan (CMGs). We have conjugated pH-sensitive variant
7 pHLIP peptide to the CMGs (V7-CMG) to provide targeting specificity
to the acidic tumor microenvironment. In vitro, treatment of S2VP10
and MiaPaca2 cells with V7-CMG containing gemcitabine resulted in
significantly greater cytotoxicity with 97% and 96.5% cell death,
respectively than gemcitabine alone 60% and 76% death at pH 6.5 (S2VP10
pH 6.5 p = 0.009; MiaPaca2 pH 6.5 p = 0.0197). In vivo, the V7-CMGs
provided the contrast and targeting specificity necessary for MSOT
of retroperitoneal orthotopic pancreatic tumors. In the in vivo S2VP10
model, the V7-CMG particle preferentially accumulated within the tumor
at 17.1 MSOT a.u. signal compared with 0.7 MSOT a.u. in untargeted
CMG control in tumor (<i>P</i> = 0.0002). Similarly, V7-CMG
signal was 9.34 MSOT a.u. in the S2013 model compared with untargeted
CMG signal at 0.15 MSOT a.u. (<i>P</i> = 0.0004). The pH-sensitivity
of the targeting pHLIP peptide and chitosan coating makes the particles
suitable for simultaneous in vivo tumor imaging and drug delivery