Extracellular Vesicles Derived from Induced Pluripotent Stem Cells Promote Renoprotection in Acute Kidney Injury Model

Abstract

Induced pluripotent stem cells (iPSC) have been the focus of several studies due to their wide range of application, including in cellular therapy. The use of iPSC in regenerative medicine is limited by their tumorigenic potential. Extracellular vesicles (EV) derived from stem cells have been shown to support renal recovery after injury. However, no investigation has explored the potential of iPSC-EV in the treatment of kidney diseases. To evaluate this potential, we submitted renal tubule cells to hypoxia-reoxygenation injury, and we analyzed cell death rate and changes in functional mitochondria mass. An in vivo model of ischemia-reperfusion injury was used to evaluate morphological and functional alterations. Gene array profile was applied to investigate the mechanism involved in iPSC-EV effects. In addition, EV derived from adipose mesenchymal cells (ASC-EV) were also used to compare the potential of iPSC-EV in support of tissue recovery. The results showed that iPSC-EV were capable of reducing cell death and inflammatory response with similar efficacy than ASC-EV. Moreover, iPSC-EV protected functional mitochondria and regulated several genes associated with oxidative stress. Taken together, these results show that iPSC can be an alternative source of EV in the treatment of different aspects of kidney disease.

Therapeutic Potential of Human Induced Pluripotent Stem Cells and Renal Progenitor Cells in Experimental Chronic Kidney Disease

“…The reduced renal brosis was corroborated by a decreased expression of α-SMA staining in the treated groups, suggesting that both cell treatments were able to reduce the brosis associated with end stage kidney disease. In addition, we demonstrated that the hiPSC treatment decreased macrophage CD68+ cells in the renal parenchyma, possibly due to a paracrine antiin ammatory effect [33,35]. Previous studies lend support to the present observation since it has been reported that mouse kidney progenitor-like cells reduce interstitial brosis, glomerular sclerosis, recruitment of macrophages and myo broblasts in the interstitium, as well as the blood pressure levels in 5/6 CKD model [18].…”

“…A similar improvement in renal function was also described by some authors using iPSCs and hiPSC-derived renal progenitors [33,34]. The mechanisms underlying this selective bene cial effect of hiPSCs over the RPC could be due to the release of cytokines and renoprotective factors released by this cell type, as previously reported [33,35]. Both iPSC and RPCs reduced the histological damage observed in CKD.…”

“…Some mechanisms have been proposed to explain the bene cial effect of cell therapy on improving renal injury, especially with the use of iPSCs and RPCs [2,17,18,22,[33][34][35][36][37][38][39]. RPCs can differentiate in vivo by forming renal tubules and acting through pro-proliferative, anti-apoptotic and anti-in ammatory effects [22], as well as by integrating into the kidney [17], decreasing the level of vascular rarefaction and preventing endothelial mesenchymal transition [18].…”

Extracellular Vesicles: The New Frontier of Stem Cell Regenerative Medicine?

“…Furthermore, iPSC-EVs have been involved in immune response modulation, with a decrease in infiltrating macrophages, and in inflammation modulation, through macrophage M2 polarization. A modulation of oxidative stress was also observed [203].…”

“…Lee and co-workers have already demonstrated that also iPSCs can protect kidney through the induction of an anti-apoptotic, anti-inflammatory and antioxidant response [202]. Collino et al evaluated the protective and regenerative potential of iPSC-EVs in an acute kidney injury model to explore the possibility of their use in kidney regenerative medicine [203]. In their study the authors demonstrated that the main mechanism associated with mitochondria protection.…”