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postgraduate thesis: Role of mesenchymal stem cells in proteinuric nephropathy
Title | Role of mesenchymal stem cells in proteinuric nephropathy |
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Authors | |
Advisors | |
Issue Date | 2014 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Wu, H. [吳浩佳]. (2014). Role of mesenchymal stem cells in proteinuric nephropathy. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5270555 |
Abstract | Proteinuria has been recognized as a common feature in many forms of chronic kidney disease (CKD). As traditional medications for proteinuric nephropathy, such as blockade of the renin-angiotensin system (RAS), has only achieved limited clinical success, more effective renoprotective strategies need to be explored. Bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) have recently shown promise as a therapeutic tool in acute kidney injury (AKI) models. The therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in proteinuric nephropathy models is unknown.
Using a co-culture model of human proximal tubular epithelial cells (PTECs) and BM-MSCs, I first examined the potential effect of BM-MSCs in albumin-induced pro-inflammatory response and epithelial-to-mesenchymal transition (EMT) in PTECs. The unstimulated BM-MSCs exerted moderate suppressive effect on tubular inflammation as only albumin-induced CCL-2 and CCL-5 expression was attenuated in PTECs. When concomitantly stimulated by albumin excess, however, BM-MSCs remarkably suppressed albumin-induced tubular IL-6, IL-8, TNF-α, CCL-2, and CCL-5 expression, suggesting albumin overloaded milieu to be a prerequisite for them to fully exhibit their anti-inflammatory effects. This effect was mediated via deactivation of tubular NF-κB signaling as BM-MSCs prevented the overexpression of p-IκB and nuclear translocation of NF-κB. In addition, albumin-induced tubular EMT, as shown by the loss of E-cadherin and induction of α-SMA, FN-1 and collagen IV in PTECs, was also prevented by BM-MSC co-culture.
To dissect the mechanism of action, I next explored the paracrine factors secreted by BM-MSCs under an albumin-overloaded condition and studied their contribution to the protective effect on tubular inflammation and EMT. Albumin-overloaded BM-MSCs per se overexpressed 34 paracrine factors, of which hepatocyte growth factor (HGF) and TNFα-stimulating gene (TSG)-6 were regulated by P38 and NF-κB signaling. These paracrine factors suppressed both the proinflammatory and profibrotic phenotypes in albumin-induced PTECs. Neutralizing HGF and TSG-6 abolished the anti-inflammatory and anti-EMT effects of BM-MSC co-culture in albumin-induced PTECs, respectively.
Finally, in albumin-overloaded mice, a well established murine model reminiscent of human CKD, treatment with mouse BM-MSCs markedly reduced BUN, tubular CCL-2 and CCL-5 expression, interstitial macrophage, α-SMA and collagen IV accumulation independent of changes in proteinuria, together with upregulated renal cortical expression of HGF. Exogenous BM-MSCs were detected in their kidneys by PKH-26 staining. Collectively, these in vitro and in vivo data suggest a modulatory effect of BM-MSCs on albumin-induced tubular inflammation and fibrosis and underscore a therapeutic potential of BM-MSCs for CKD in the future. |
Degree | Doctor of Philosophy |
Subject | Proteinuria - Treatment Kidneys - Diseases - Treatment Mesenchymal stem cells |
Dept/Program | Medicine |
Persistent Identifier | http://hdl.handle.net/10722/206678 |
HKU Library Item ID | b5270555 |
DC Field | Value | Language |
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dc.contributor.advisor | Lai, KN | - |
dc.contributor.advisor | Tang, SCW | - |
dc.contributor.author | Wu, Haojia | - |
dc.contributor.author | 吳浩佳 | - |
dc.date.accessioned | 2014-11-25T03:53:16Z | - |
dc.date.available | 2014-11-25T03:53:16Z | - |
dc.date.issued | 2014 | - |
dc.identifier.citation | Wu, H. [吳浩佳]. (2014). Role of mesenchymal stem cells in proteinuric nephropathy. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b5270555 | - |
dc.identifier.uri | http://hdl.handle.net/10722/206678 | - |
dc.description.abstract | Proteinuria has been recognized as a common feature in many forms of chronic kidney disease (CKD). As traditional medications for proteinuric nephropathy, such as blockade of the renin-angiotensin system (RAS), has only achieved limited clinical success, more effective renoprotective strategies need to be explored. Bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) have recently shown promise as a therapeutic tool in acute kidney injury (AKI) models. The therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in proteinuric nephropathy models is unknown. Using a co-culture model of human proximal tubular epithelial cells (PTECs) and BM-MSCs, I first examined the potential effect of BM-MSCs in albumin-induced pro-inflammatory response and epithelial-to-mesenchymal transition (EMT) in PTECs. The unstimulated BM-MSCs exerted moderate suppressive effect on tubular inflammation as only albumin-induced CCL-2 and CCL-5 expression was attenuated in PTECs. When concomitantly stimulated by albumin excess, however, BM-MSCs remarkably suppressed albumin-induced tubular IL-6, IL-8, TNF-α, CCL-2, and CCL-5 expression, suggesting albumin overloaded milieu to be a prerequisite for them to fully exhibit their anti-inflammatory effects. This effect was mediated via deactivation of tubular NF-κB signaling as BM-MSCs prevented the overexpression of p-IκB and nuclear translocation of NF-κB. In addition, albumin-induced tubular EMT, as shown by the loss of E-cadherin and induction of α-SMA, FN-1 and collagen IV in PTECs, was also prevented by BM-MSC co-culture. To dissect the mechanism of action, I next explored the paracrine factors secreted by BM-MSCs under an albumin-overloaded condition and studied their contribution to the protective effect on tubular inflammation and EMT. Albumin-overloaded BM-MSCs per se overexpressed 34 paracrine factors, of which hepatocyte growth factor (HGF) and TNFα-stimulating gene (TSG)-6 were regulated by P38 and NF-κB signaling. These paracrine factors suppressed both the proinflammatory and profibrotic phenotypes in albumin-induced PTECs. Neutralizing HGF and TSG-6 abolished the anti-inflammatory and anti-EMT effects of BM-MSC co-culture in albumin-induced PTECs, respectively. Finally, in albumin-overloaded mice, a well established murine model reminiscent of human CKD, treatment with mouse BM-MSCs markedly reduced BUN, tubular CCL-2 and CCL-5 expression, interstitial macrophage, α-SMA and collagen IV accumulation independent of changes in proteinuria, together with upregulated renal cortical expression of HGF. Exogenous BM-MSCs were detected in their kidneys by PKH-26 staining. Collectively, these in vitro and in vivo data suggest a modulatory effect of BM-MSCs on albumin-induced tubular inflammation and fibrosis and underscore a therapeutic potential of BM-MSCs for CKD in the future. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Proteinuria - Treatment | - |
dc.subject.lcsh | Kidneys - Diseases - Treatment | - |
dc.subject.lcsh | Mesenchymal stem cells | - |
dc.title | Role of mesenchymal stem cells in proteinuric nephropathy | - |
dc.type | PG_Thesis | - |
dc.identifier.hkul | b5270555 | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Medicine | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.5353/th_b5270555 | - |
dc.identifier.mmsid | 991038815009703414 | - |