Inhibin-A and Decorin Secreted by Human Adult Renal Stem/Progenitor Cells Through the TLR2 Engagement Induce Renal Tubular Cell Regeneration

Abstract

Acute kidney injury (AKI) is a public health problem worldwide. Several therapeutic strategies have been made to accelerate recovery and improve renal survival. Recent studies have shown that human adult renal progenitor cells (ARPCs) participate in kidney repair processes, and may be used as a possible treatment to promote regeneration in acute kidney injury. Here, we show that human tubular ARPCs (tARPCs) protect physically injured or chemically damaged renal proximal tubular epithelial cells (RPTECs) by preventing cisplatin-induced apoptosis and enhancing proliferation of survived cells. tARPCs without toll-like receptor 2 (TLR2) expression or TLR2 blocking completely abrogated this regenerative effect. Only tARPCs, and not glomerular ARPCs, were able to induce tubular cell regeneration process and it occurred only after damage detection. Moreover, we have found that ARPCs secreted inhibin-A and decorin following the RPTEC damage and that these secreted factors were directly involved in cell regeneration process. Polysaccharide synthetic vesicles containing these molecules were constructed and co-cultured with cisplatin damaged RPTECs. These synthetic vesicles were not only incorporated into the cells, but they were also able to induce a substantial increase in cell number and viability. The findings of this study increase the knowledge of renal repair processes and may be the first step in the development of new specific therapeutic strategies for renal repair.

Renal progenitor cells revert LPS‐induced endothelial‐to‐mesenchymal transition by secreting CXCL6, SAA4, and BPIFA2 antiseptic peptides

“…Among the several disorders encountered in sepsis, AKI is the major complication and is mainly characterized by dysfunction of ECs that acquire a myofibroblast phenotype by EndMT, contributing to the renal fibrosis (26)(27)(28). Here, we investigated the effects of ARPCs on endothelial dysfunction, and for the first time we found that ARPCs, in addition to their ability to repair damaged renal tubular cells (18) and regenerate renal tubules and glomeruli (23), can also revert the sepsis-induced EndMT process that contributes to the accumulation of activated fibroblasts and myofibroblasts in kidney fibrosis (29)(30)(31)(32). In fact, following LPS stimulation, ARPCs restored constitutive endothelial and dysfunctional fibroblastic CD31, VE-cadherin, collagen I, and vimentin markers to basal levels.…”

“…Therefore, once again, ARPCs proved to be capable of producing a precise positive effect through a paracrine mechanism. Additionally, the secreted molecules are different and specific for a particular damage setting; in the case of physical or chemical damage on RPTECs, renal progenitors secreted regenerative molecules such as inhibin-A and decorin (18), whereas in the case of a septic shock, they secreted CXCL6, SAA4, and BPIFA2. The last chemokines belong to an antimicrobial peptide family that attenuates local inflammatory response and decreases the systemic toxicity of endotoxins (33).…”

“…For in vitro experiments, cells were plated at a density of 10,000 cells/cm 2 , and 48 h later, they were incubated in medium alone or stimulated with LPS 4 mg/ml (MilliporeSigma, Burlington, MA, USA), BPIFA2 4 ng/ml (Sino Biological, Beijing, China), SAA4 20 ng/ml, CXCL6 2.5 ng/ml, or SAA2 5 ng/ml (OriGene, Rockville, MD). For coculture experiments, ARPCs were seeded on the top of 0.4-mm-thick polycarbonate Transwell plates (Costar; Corning, Corning, NY, USA) at a density of 8000 cells/cm 2 and were used for cocultures after 48 h. For TLR4 and TLR2 inhibition assays, 4 mg/ml mouse monoclonal anti-TLR4 (Abcam, Cambridge, United Kingdom) or 0.4 mg/ml mouse monoclonal anti-TLR2 (Santa Cruz Biotechnology, Dallas, TX, USA) (18) were respectively preincubated alone for 1 h before coculture with ECs and then washed out.…”

“…Of note, human adult renal stem/progenitor cells (ARPCs) enhance the tubular regenerative mechanism during AKI and could be considered an alternative approach in the treatment of kidney diseases for their multipotent differentiation ability and for their reparative properties (18)(19)(20)(21)(22). Renal progenitors can induce the renewal of renal tissue, directly regenerating damaged cells (23) and also repairing physical or chemical damage in renal tubular cells through paracrine effects following TLR2-mediated activation (18,19).…”

Decorin Protects Cardiac Myocytes against Simulated Ischemia/Reperfusion Injury

“…Gaspar et al showed that pharmacological blockade of Toll-like receptor 4 (TLR-4) signaling and its downstream signaling contributors (IRAK1/4, ERK, JNK and p38 MAP kinases) abolished the cytoprotective effect of exogenously administered recombinant biglycan core protein against SI/R injury [6]. In another study, decorin secreted by human adult renal stem cells through the TLR-2 receptor induce renal tubular cell regeneration [27].…”