Stem cells in the treatment of renal fibrosis: a review of preclinical and clinical studies of renal fibrosis pathogenesis

Abstract

Renal fibrosis commonly leads to glomerulosclerosis and renal interstitial fibrosis and the main pathological basis involves tubular atrophy and the abnormal increase and excessive deposition of extracellular matrix (ECM). Renal fibrosis can progress to chronic kidney disease. Stem cells have multilineage differentiation potential under appropriate conditions and are easy to obtain. At present, there have been some studies showing that stem cells can alleviate the accumulation of ECM and renal fibrosis. However, the sources of stem cells and the types of renal fibrosis or renal fibrosis models used in these studies have differed. In this review, we summarize the pathogenesis (including signaling pathways) of renal fibrosis, and the effect of stem cell therapy on renal fibrosis as described in preclinical and clinical studies. We found that stem cells from various sources have certain effects on improving renal function and alleviating renal fibrosis. However, additional clinical studies should be conducted to confirm this conclusion in the future.

Is the Macrophage Phenotype Determinant for Fibrosis Development?

“…Kidney fibrosis, as previously described for other scenarios, is an excessive pathological response characterized by increased wound healing and consequently, a great deposition and accumulation of ECM [ 137 ]. Such an increase in fibrotic tissue is frequently localized, in the space between tubules and peritubular capillaries, known as renal interstitial fibrosis [ 138 ], or in the glomerulus, leading to glomerulosclerosis [ 139 ]. As a result, atrophy of renal tissue, as well as narrowing of capillaries predominantly emerges.…”

“…As a result, atrophy of renal tissue, as well as narrowing of capillaries predominantly emerges. Indeed, this pathological response commonly appears in many chronic kidney diseases including diabetic nephropathy, hypertensive nephropathy, primary chronic glomerulonephritis, chronic interstitial glomerulonephritis, and chronic tubular disease, and may be the cause of renal failure and death [ 138 , 139 ]. Therefore, renal fibrosis arises as an attempt to repair the tissue in a context of chronic kidney inflammation, which may initiate as a response to different stimuli such as toxins, xenobiotics, infections, or genetic disorders, and become pathologically persistent [ 140 ], predisposing the patient to develop any form of the chronic kidney diseases previously mentioned [ 141 ].…”

“…Again, among the wide variety of substances and stimuli that participate in myofibroblast activation, macrophages are commonly involved. Indeed, macrophages themselves can even transdifferentiate into active myofibroblasts in a process known as MMT [ 139 ]. In the renal environment, as immune cells, macrophages play a crucial role in the inflammatory response as well as tissue repair.…”

“…Of interest, the MyD88-mediated signaling pathway participates in the recruitment of M2 macrophages, specifically the IL-10+CD206+CD11b high subtype, in a UUO model, contributing to collagen deposition [ 162 ]. Furthermore, it has been widely described that the Notch signaling pathway in macrophages is involved in renal fibrosis [ 139 ]. In line with this, Jiang et al demonstrated that inhibiting the transcription factor recombination signal binding protein-Jκ (RBP-J), which is involved in the activation of the Notch pathway, decreased macrophage recruitment and further activation, thus improving renal fibrosis [ 163 ].…”

Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis

“…Renal interstitial fibrosis is mainly driven by various pro-fibrotic growth factors, forming a fibrotic microenvironment in the interstitial space (Chen et al, 2018c;Tang et al, 2019). In other words, the major pathological events of renal fibrosis include inflammatory cell infiltration, fibroblast activation and proliferation, and abnormal increase and excessive deposition of extracellular matrix (ECM) components, mainly composed of collagen, fibronectin, and proteoglycans (Liu et al, 2021). With the ECM continuous deposition, scar tissue replaces normal tissue, tubules, and peritubular capillaries are lost, resulting in disruption of tissue architecture and loss of renal function (Xing et al, 2021).…”