Rat Mesenchymal Stromal Cell Sheets Suppress Renal Fibrosis via Microvascular Protection

Abstract

Renal fibrosis is one of the largest global health care problems, and microvascular (MV) injury is important in the development of progressive fibrosis. Although conventional cell therapy suppresses kidney injury via the role of vasoprotective cytokines, the effects are limited due to low retention of administered cells. We recently described that transplantation of hepatocyte growth factor (HGF)transgenic mesothelial cell sheets showed a remarkable cell survival and strong therapeutic effects in a rat renal fibrosis model. Due to the translational hurdles of transgenic cells, we here applied this technique for allogeneic transplantation using rat bone marrow mesenchymal stromal cells (MSCs). MSC sheets were transplanted onto the kidney surface of a rat renal ischemia-reperfusion-injury model and the effects were compared between those in untreated rats and those receiving intravenous (IV) administration of the cells. We found that donor-cell survival was superior in the cell sheet group relative to the IV group, and that the cell sheets secreted HGF and vascular endothelial growth factor (VEGF) up to day 14. Transplantation of cell sheets increased the expression of activated HGF/VEGF receptors in the kidney. There was no evidence of migration of transplanted cells into the kidney parenchyma. Additionally, the cell sheets significantly suppressed renal dysfunction, MV injury, and fibrosis as compared with that observed in the untreated and IV groups. Furthermore, we demonstrated that the MSC sheet protected MV density in the whole kidney according to threedimensional microcomputed tomography. In conclusion, MSC sheets strongly prevented renal fibrosis via MV protection, suggesting that this strategy represents a potential novel therapy for various kidney diseases. STEM CELLS TRANSLATIONAL MEDICINE 2019;8:1330-1341 SIGNIFICANCE STATEMENTCell therapy has been applied to various diseases that are resistant to conventional therapy. Renal fibrosis is one of the most difficult issues, and many researchers have tried intravascular administration of stem cells. The present study revealed that transplantation of mesenchymal stromal cell (MSC) sheets onto the kidney showed dramatic effects, including long-term cell survival, amelioration of kidney dysfunction, vasoprotection, and antifibrosis, compared with intravenous administration of MSCs. These results suggest that cell sheet technology improves the effects of cell therapy in various aspects. Therefore, cell sheet therapy could be a potential novel therapeutic approach for various kidney diseases in the future.

<p>Emodin Retarded Renal Fibrosis Through Regulating HGF and TGFβ–Smad Signaling Pathway</p>

“…In this research, we sought to detect the antifibrotic effect of combination treatment. It has been confirmed that transplantation of HGF-transgenic mesothelial cell sheets show therapeutic effects on renal fibrosis 26 and can be used as an antifibrotic agent. 27 The present study verified that HGF suppressed the progression of renal fibrosis at different concentrations.…”

Cell Sheets Restore Secretory Function in Wounded Mouse Submandibular Glands

“…Specifically, a wounded skin mouse model treated with mesenchymal stem cell sheets formed organized blood vessels and exhibited increased expression of angiogenic factors, thus leading to tissue healing at twenty-one days post-surgery [ 63 ]. Likewise, mesenchymal stem cell sheets were shown to improve kidney function by reducing fibrosis and microvasculature damage in a renal ischemia-reperfusion injury rat model fourteen days post-surgery [ 64 ]. Furthermore, mesenchymal stem cell sheets have been shown to restore function, while decreasing fibrosis in a chronic liver injury mouse model nine days after surgery [ 65 ].…”

Advances in the Application of Biomimetic Endometrium Interfaces for Uterine Bioengineering in Female Infertility

“…However, in real practices, the collection of endometrial cells is not a recommended option because it is hard to collect adequate quantity of endometrial cells from the uterus and collection may also be interfered by certain inflammatory or contagious diseases, apart from the harm out of invasive procedures (Logan et al, 2018). Stem cell sheet engineering (SCSE) gradually becomes an important research direction due to the minimal invasiveness, autologous tissue supply, multi-differentiation potential, high proliferation, growth factor secretion and signaling transduction of stem cells (Shum et al, 2017;Hsu et al, 2019;Imafuku et al, 2019).…”