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Transplantation of induced pluripotent stem cell-derived renal stem cells improved acute kidney injury.

Li Q, Tian SF, Guo Y, Niu X, Hu B, Guo SC, Wang NS, Wang Y - Cell Biosci (2015)

Bottom Line: However, the therapeutic effect of iPSC-derived RPCs for AKI has yet to be determined.We then established the rat ischemia-reperfusion injury (IR) model and transplanted the iPSC-derived RPCs into the injured rats in combination with the hydrogel.Our results revealed that iPSC-derived RPCs can protect AKI rat from renal function impairment and severe tubular injury by up-regulating the renal tubules formation, promoting cell proliferation, reducing apoptosis, and regulating the microenvironment in the injured kidney.

View Article: PubMed Central - PubMed

Affiliation: Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233 China.

ABSTRACT

Background: Acute kidney injury (AKI) is a severe disease with high morbidity and mortality. Methods that promote repair of the injured kidney have been extensively investigated. Cell-based therapy with mesenchymal stem cells or renal progenitor cells (RPCs) resident in the kidney has appeared to be an effective strategy for the treatment of AKI. Embryonic stem cells or induced pluripotent stem cells (iPSCs) are also utilized for AKI recovery. However, the therapeutic effect of iPSC-derived RPCs for AKI has yet to be determined.

Methods: In this study, we induced iPSCs differentiation into RPCs using a nephrogenic cocktail of factors combined with the renal epithelial cell growth medium. We then established the rat ischemia-reperfusion injury (IR) model and transplanted the iPSC-derived RPCs into the injured rats in combination with the hydrogel. Next, we examined the renal function-related markers and renal histology to assess the therapeutic effect of the injected cells. Moreover, we investigated the mechanism by which iPSC-derived RPCs affect AKI caused by IR.

Results: We showed that the differentiation efficiency of iPSCs to RPCs increased when cultured with renal epithelial cell growth medium after stimulation with a nephrogenic cocktail of factors. The transplantation of iPSC-derived RPCs decreased the levels of biomarkers indicative of renal injury and attenuated the necrosis and apoptosis of renal tissues, but resulted in the up-regulation of renal tubules formation, cell proliferation, and the expression of pro-renal factors.

Conclusion: Our results revealed that iPSC-derived RPCs can protect AKI rat from renal function impairment and severe tubular injury by up-regulating the renal tubules formation, promoting cell proliferation, reducing apoptosis, and regulating the microenvironment in the injured kidney.

No MeSH data available.


Related in: MedlinePlus

Anti-inflammatory factors and pro-renal tubular repair factors increased after renal progenitor cell transplantation. Real-time PCR analysis of the expression of anti-inflammatory factors (IL-10, FGF, and TGF-β) and pro-renal tubular repair factors (EGF, HGF, and PDGF) on D3, D7, D14, and D28. The anti-inflammatory factors and pro-renal tubular repair factors in the renal cortex of rats after cell transplantation are up-regulated compared with the levels observed in the control group. *P < 0.05 vs. IR-Control
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Fig5: Anti-inflammatory factors and pro-renal tubular repair factors increased after renal progenitor cell transplantation. Real-time PCR analysis of the expression of anti-inflammatory factors (IL-10, FGF, and TGF-β) and pro-renal tubular repair factors (EGF, HGF, and PDGF) on D3, D7, D14, and D28. The anti-inflammatory factors and pro-renal tubular repair factors in the renal cortex of rats after cell transplantation are up-regulated compared with the levels observed in the control group. *P < 0.05 vs. IR-Control

Mentions: We further investigated the mechanism through which RPCs relieve acute renal injury caused by IR. Previous studies have reported that mouse kidney progenitor cells accelerate renal regeneration after ischemic injury by differentiation into epithelial cells and incorporating into the renal tubule [9, 23–25]. Thus, we first examined the localization of the transplanted iPSC-derived RPCs. Because the iPS cell line used in our study carries a ubiquitously expressed gfp gene, it is convenient to trace the injected cells. Using immunohistochemistry, we showed that GFP-positive cells began to form a tubular structure in the recipient kidney 7 days after injection (Fig. 3c). Importantly, no tumor was detected even 3 months after transplantation. Next, the effects of the RPCs on the proliferation and apoptosis of cells in the injured kidney were examined by PCNA staining and TUNEL analyses, respectively. The results showed that the number of PCNA-positive cells increased in the transplanted group compared with that found in the control group on days 7 after injection (Fig. 4a, b), indicating the presence of a greater number of proliferating renal tubular epithelial cells in the kidney after RPC transplantation. In contrast, the cell apoptosis on days 7 was reduced in the RPC-transplanted group, as shown by TUNEL analysis (Fig. 4c, d). Furthermore, we detected the expression levels of the anti-inflammatory factors interleukin-10 (IL-10), basic fibroblast growth factor (bFGF), and transforming growth factor β1 (TGF-β1) and growth factors promoting renal tubular cell repair, namely epidermal growth factor (EGF), hepatocyte growth factor (HGF), and platelet-derived growth factor (PDGF). The real-time PCR analysis showed that the expression of these genes was upregulated to different extents after RPC transplantation (Fig. 5). Altogether, these data indicate that iPSC-derived RPC transplantation improves renal function after IR by directly incorporating into the renal tubule, promoting cell proliferation, reducing apoptosis, and upregulating the expression of pro-renal factors.Fig. 4


Transplantation of induced pluripotent stem cell-derived renal stem cells improved acute kidney injury.

Li Q, Tian SF, Guo Y, Niu X, Hu B, Guo SC, Wang NS, Wang Y - Cell Biosci (2015)

Anti-inflammatory factors and pro-renal tubular repair factors increased after renal progenitor cell transplantation. Real-time PCR analysis of the expression of anti-inflammatory factors (IL-10, FGF, and TGF-β) and pro-renal tubular repair factors (EGF, HGF, and PDGF) on D3, D7, D14, and D28. The anti-inflammatory factors and pro-renal tubular repair factors in the renal cortex of rats after cell transplantation are up-regulated compared with the levels observed in the control group. *P < 0.05 vs. IR-Control
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4541730&req=5

Fig5: Anti-inflammatory factors and pro-renal tubular repair factors increased after renal progenitor cell transplantation. Real-time PCR analysis of the expression of anti-inflammatory factors (IL-10, FGF, and TGF-β) and pro-renal tubular repair factors (EGF, HGF, and PDGF) on D3, D7, D14, and D28. The anti-inflammatory factors and pro-renal tubular repair factors in the renal cortex of rats after cell transplantation are up-regulated compared with the levels observed in the control group. *P < 0.05 vs. IR-Control
Mentions: We further investigated the mechanism through which RPCs relieve acute renal injury caused by IR. Previous studies have reported that mouse kidney progenitor cells accelerate renal regeneration after ischemic injury by differentiation into epithelial cells and incorporating into the renal tubule [9, 23–25]. Thus, we first examined the localization of the transplanted iPSC-derived RPCs. Because the iPS cell line used in our study carries a ubiquitously expressed gfp gene, it is convenient to trace the injected cells. Using immunohistochemistry, we showed that GFP-positive cells began to form a tubular structure in the recipient kidney 7 days after injection (Fig. 3c). Importantly, no tumor was detected even 3 months after transplantation. Next, the effects of the RPCs on the proliferation and apoptosis of cells in the injured kidney were examined by PCNA staining and TUNEL analyses, respectively. The results showed that the number of PCNA-positive cells increased in the transplanted group compared with that found in the control group on days 7 after injection (Fig. 4a, b), indicating the presence of a greater number of proliferating renal tubular epithelial cells in the kidney after RPC transplantation. In contrast, the cell apoptosis on days 7 was reduced in the RPC-transplanted group, as shown by TUNEL analysis (Fig. 4c, d). Furthermore, we detected the expression levels of the anti-inflammatory factors interleukin-10 (IL-10), basic fibroblast growth factor (bFGF), and transforming growth factor β1 (TGF-β1) and growth factors promoting renal tubular cell repair, namely epidermal growth factor (EGF), hepatocyte growth factor (HGF), and platelet-derived growth factor (PDGF). The real-time PCR analysis showed that the expression of these genes was upregulated to different extents after RPC transplantation (Fig. 5). Altogether, these data indicate that iPSC-derived RPC transplantation improves renal function after IR by directly incorporating into the renal tubule, promoting cell proliferation, reducing apoptosis, and upregulating the expression of pro-renal factors.Fig. 4

Bottom Line: However, the therapeutic effect of iPSC-derived RPCs for AKI has yet to be determined.We then established the rat ischemia-reperfusion injury (IR) model and transplanted the iPSC-derived RPCs into the injured rats in combination with the hydrogel.Our results revealed that iPSC-derived RPCs can protect AKI rat from renal function impairment and severe tubular injury by up-regulating the renal tubules formation, promoting cell proliferation, reducing apoptosis, and regulating the microenvironment in the injured kidney.

View Article: PubMed Central - PubMed

Affiliation: Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233 China.

ABSTRACT

Background: Acute kidney injury (AKI) is a severe disease with high morbidity and mortality. Methods that promote repair of the injured kidney have been extensively investigated. Cell-based therapy with mesenchymal stem cells or renal progenitor cells (RPCs) resident in the kidney has appeared to be an effective strategy for the treatment of AKI. Embryonic stem cells or induced pluripotent stem cells (iPSCs) are also utilized for AKI recovery. However, the therapeutic effect of iPSC-derived RPCs for AKI has yet to be determined.

Methods: In this study, we induced iPSCs differentiation into RPCs using a nephrogenic cocktail of factors combined with the renal epithelial cell growth medium. We then established the rat ischemia-reperfusion injury (IR) model and transplanted the iPSC-derived RPCs into the injured rats in combination with the hydrogel. Next, we examined the renal function-related markers and renal histology to assess the therapeutic effect of the injected cells. Moreover, we investigated the mechanism by which iPSC-derived RPCs affect AKI caused by IR.

Results: We showed that the differentiation efficiency of iPSCs to RPCs increased when cultured with renal epithelial cell growth medium after stimulation with a nephrogenic cocktail of factors. The transplantation of iPSC-derived RPCs decreased the levels of biomarkers indicative of renal injury and attenuated the necrosis and apoptosis of renal tissues, but resulted in the up-regulation of renal tubules formation, cell proliferation, and the expression of pro-renal factors.

Conclusion: Our results revealed that iPSC-derived RPCs can protect AKI rat from renal function impairment and severe tubular injury by up-regulating the renal tubules formation, promoting cell proliferation, reducing apoptosis, and regulating the microenvironment in the injured kidney.

No MeSH data available.


Related in: MedlinePlus