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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

Transplantation of iPSC-derived renal progenitor cells improved renal tubular damage caused by ischemia–reperfusion. a Pathological changes in the kidney on the third day after surgery, as shown by H&E staining. Luminal debris, loss of brush borders and lumen expansion are observed in the injured groups (black arrow). b The transplantation of iPSC-derived renal progenitor cells reduced the acute tubular necrosis scores. c The immunohistochemistry analysis indicated that the injected GFP-positive cells formed a tubular structure (black arrow) in the recipient organ at the indicated times after transplantation. *P < 0.05 vs. IR-Control. Scale bar 50 μm
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Fig3: Transplantation of iPSC-derived renal progenitor cells improved renal tubular damage caused by ischemia–reperfusion. a Pathological changes in the kidney on the third day after surgery, as shown by H&E staining. Luminal debris, loss of brush borders and lumen expansion are observed in the injured groups (black arrow). b The transplantation of iPSC-derived renal progenitor cells reduced the acute tubular necrosis scores. c The immunohistochemistry analysis indicated that the injected GFP-positive cells formed a tubular structure (black arrow) in the recipient organ at the indicated times after transplantation. *P < 0.05 vs. IR-Control. Scale bar 50 μm

Mentions: Next, the rat IR model was generated by occlusion of the left renal artery followed by reperfusion and right kidney removal. iPSC-derived RPCs from the RAB + REGM group were injected directly into the renal parenchyma of the injured rats in combination with the hydrogel. The control group (IR-control) was injected with PBS combined with the hydrogel. The levels of BUN and Scr were detected at the indicated times. The plasma levels of BUN and Scr reached their peak levels at day 1 of renal IR in all groups and then decreased gradually (Fig. 2a, b). After RPC transplantation, the plasma levels of BUN and Scr were lower than those of the IR-control group (Fig. 2a, b). To test whether the RPC transplantation has beneficial effects on regeneration after IR, the rats were sacrificed on days 3, 7, 14, and 28, and the renal histology was examined. H&E staining showed that the proximal tubule in the renal cortex in the control group exhibited acute injury and necrosis 3 days after surgery (Fig. 3a): the brush border of some epithelial cells disappeared; the lumen expanded; some of the tubular epithelial cells detached from the basement membrane; the tubule was obstructed with cellular debris; and the interstitial tubule was infiltrated with inflammatory cells. The histological features of necrotic injury were still severe 7 days after ischemia and began to improve on days 14 and 28. The injury phenotype was decreased in the rat kidney as a result of RPC transplantation. The quantitative analysis of the renal tubular necrosis using the grading scores of Paller et al. [22] is shown in Fig. 3b. These results suggest that the transplantation of iPSC-derived RPCs could improve renal regeneration and function after AKI.Fig. 2


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)

Transplantation of iPSC-derived renal progenitor cells improved renal tubular damage caused by ischemia–reperfusion. a Pathological changes in the kidney on the third day after surgery, as shown by H&E staining. Luminal debris, loss of brush borders and lumen expansion are observed in the injured groups (black arrow). b The transplantation of iPSC-derived renal progenitor cells reduced the acute tubular necrosis scores. c The immunohistochemistry analysis indicated that the injected GFP-positive cells formed a tubular structure (black arrow) in the recipient organ at the indicated times after transplantation. *P < 0.05 vs. IR-Control. Scale bar 50 μm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Transplantation of iPSC-derived renal progenitor cells improved renal tubular damage caused by ischemia–reperfusion. a Pathological changes in the kidney on the third day after surgery, as shown by H&E staining. Luminal debris, loss of brush borders and lumen expansion are observed in the injured groups (black arrow). b The transplantation of iPSC-derived renal progenitor cells reduced the acute tubular necrosis scores. c The immunohistochemistry analysis indicated that the injected GFP-positive cells formed a tubular structure (black arrow) in the recipient organ at the indicated times after transplantation. *P < 0.05 vs. IR-Control. Scale bar 50 μm
Mentions: Next, the rat IR model was generated by occlusion of the left renal artery followed by reperfusion and right kidney removal. iPSC-derived RPCs from the RAB + REGM group were injected directly into the renal parenchyma of the injured rats in combination with the hydrogel. The control group (IR-control) was injected with PBS combined with the hydrogel. The levels of BUN and Scr were detected at the indicated times. The plasma levels of BUN and Scr reached their peak levels at day 1 of renal IR in all groups and then decreased gradually (Fig. 2a, b). After RPC transplantation, the plasma levels of BUN and Scr were lower than those of the IR-control group (Fig. 2a, b). To test whether the RPC transplantation has beneficial effects on regeneration after IR, the rats were sacrificed on days 3, 7, 14, and 28, and the renal histology was examined. H&E staining showed that the proximal tubule in the renal cortex in the control group exhibited acute injury and necrosis 3 days after surgery (Fig. 3a): the brush border of some epithelial cells disappeared; the lumen expanded; some of the tubular epithelial cells detached from the basement membrane; the tubule was obstructed with cellular debris; and the interstitial tubule was infiltrated with inflammatory cells. The histological features of necrotic injury were still severe 7 days after ischemia and began to improve on days 14 and 28. The injury phenotype was decreased in the rat kidney as a result of RPC transplantation. The quantitative analysis of the renal tubular necrosis using the grading scores of Paller et al. [22] is shown in Fig. 3b. These results suggest that the transplantation of iPSC-derived RPCs could improve renal regeneration and function after AKI.Fig. 2

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