Enhancing the Therapeutic Potential of Mesenchymal Stromal Cell-Based Therapies with an Anti-Fibrotic Agent for the Treatment of Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) affects 1 in 10 members of the general population, placing these patients at an increasingly high risk of kidney failure. Despite the significant burden of CKD on various healthcare systems, there are no effective cures that reverse or even halt its progression. In recent years, human bone-marrow-derived mesenchymal stromal cells (BM-MSCs) have been recognised as a novel therapy for CKDs, owing to their well-established immunomodulatory and tissue-reparative properties in preclinical settings, and their promising safety profile that has been demonstrated in patients with CKDs from several clinical trials. However, renal fibrosis (scarring), a hallmark of CKD, has been shown to impair the viability and functionality of BM-MSCs post-transplantation. This has suggested that BM-MSCs might require a pre-treatment or adjunct therapy that can enhance the viability and therapeutic efficacy of these stromal cells in chronic disease settings. To address this, recent studies that have combined BM-MSCs with the anti-fibrotic drug serelaxin (RLX), have demonstrated the enhanced therapeutic potential of this combination therapy in normotensive and hypertensive preclinical models of CKD. In this review, a critical appraisal of the preclinical data available on the anti-fibrotic and renoprotective actions of BM-MSCs or RLX alone and when combined, as a treatment option for normotensive vs. hypertensive CKD, is discussed.

Application of mesenchymal stem cells for anti-senescence and clinical challenges

“…In order to increase the survival rate of MSCs to improve the function and therapeutic effects, MSCs can be pretreated. There are various pretreatment methods, including the incubation of cytokines or compounds, such as DHA, SNP, DPO, atorvastatin, melatonin, and the application of some supporting materials, such as thermosensitive hydrogel, chitosan-based hydrogel, fucoidan [ 203 , 211 ]. In summary, various studies have shown that MSCs have promising safety and immunosuppressive effects in the treatment of CKD.…”

Anti-Fibrotic Effect of Synthetic Noncoding Decoy ODNs for TFEB in an Animal Model of Chronic Kidney Disease

“…Fibroblast proliferation is a precursor to extracellular matrix (ECM) overproduction [ 5 ]. The underlying cellular events are complex and involve the interaction of multiple renal resident cells with infiltrating inflammatory cells as well as tubular epithelial-to-mesenchymal transition (EMT), monocyte/macrophage and T cell infiltration and cellular apoptosis, and interstitial fibroblast and glomerular mesangial cell differentiation into activated myofibroblasts [ 6 ]. Apart from EMT, several studies have demonstrated that endothelial-to-mesenchymal transition (EndoMT) also plays an important role in the recruitment of fibroblasts [ 7 , 8 ].…”

“…The injured site of the renal interstitium can be rapidly infiltrated by a large number of inflammatory cells, aggravating fibrosis [ 19 ]. After prolonged renal injury, the infiltrated inflammatory cells release excessive pro-inflammatory cytokines, such as tumor necrosis factor (TNF) -α, interleukin (IL)-1β and IL-6, to clean up tissue debris, dead cells, and invading organisms from the injured site, as well as pro-fibrotic cytokines and growth factors [ 6 , 21 , 22 , 23 ]. Once renal fibrosis develops, most patients progress to irreversible end-stage renal disease, in which kidney transplantation with dialysis is the only therapeutic option [ 22 ].…”

Special Issue “Stem Cell Biology & Regenerative Medicine”

“…Huamin zhang et al review upcoming stem cell transplantation methods for clinical application, and the results of ongoing clinical trials, to provide ideas for the clinical use of stem cell transplantation as a potential treatment for Inflammatory bowel disease (IBD), a chronic, relapsing disease that severely affects patients’ quality of life [ 25 ]. Yifang Li et al discussed in their review the preclinical data available on the anti-fibrotic and renoprotective actions of bone-marrow-derived mesenchymal stromal cells (BM-MSCs) and the anti-fibrotic drug serelaxin (RLX), alone and when combined, as a treatment option for normotensive vs. hypertensive Chronic Kidney Disease (CKD) [ 26 ].…”