Chronic kidney disease remains a major public health burden worldwide with no ideal treatment besides dialysis or kidney transplantation.1,2 Promoting kidney regeneration is a promising strategy to treat patients with end-stage renal disease. Mammalian kidney can partially repair damaged nephrons in the condition of minor injury and progress to irreversible renal fibrosis with severe injury.3,4 By contrast, axolotl (Ambystoma mexicanum) exhibits a remarkable ability to regrow multiple body parts, including its entire limbs, the tail, ocular tissues, liver, heart, and even brain.

Rationale: Mammalian renal proximal tubules can partially regenerate after acute kidney injury (AKI). However, cells participating in the renal proximal tubule regeneration remain to be elucidated. Wilms' tumor 1 (WT1) expresses in a subtype of glomeruli parietal epithelial cells (PECs) in adult kidneys, it remains unclear whether these WT1+ PECs play a role in renal regeneration/repair after AKI. Methods: Ischemia-reperfusion injury (IRI) mouse model was used to investigate the expression pattern of WT1 in the kidney after severe AKI. Conditional deletion of WT1 gene mice were generated using Pax8CreERT2 and WT1fl/fl mice to examine the function of WT1. Then, genetic cell lineage tracing and single-cell RNA sequencing were performed to illustrate that WT1+ PECs develop into WT1+ proximal tubular epithelial cells (PTECs). Furthermore, in vitro clonogenicity, direct differentiation analysis and in vivo transplantation were used to reveal the stem cell-like properties of these WT1+ PECs. Results: The expression of WT1 protein in PECs and PTECs was increased after severe AKI. Conditional deletion of WT1 gene in PTECs and PECs aggravated renal tubular injury after severe AKI. WT1+ PECs develop into WT1+ PTECs via the transient scattered tubular cell stage, and these WT1+ PECs possess specific stem cell-like properties. Conclusions: We discovered a group of WT1+ PECs that promote renal proximal tubule regeneration/repair after severe AKI, and the expression of WT1 in PECs and PTECs is essential for renal proximal tubule regeneration after severe kidney injury.

Excessive numbers of osteoclasts are responsible for inflammation-induced osteolysis. Identification of osteoclast-targeting agents may facilitate the development of a novel therapeutic approach for the treatment of pathological bone loss. Seven-amino acid truncated (7ND) protein, a mutant form of monocyte chemoattractant protein-1 (MCP-1), functions as a competitive inhibitor of MCP-1. However, the effects of 7ND protein on osteoclast differentiation remain unknown. Therefore, in the present study, the effects of 7ND protein on osteoclast differentiation induced by tumour necrosis factor superfamily member 11 were investigated. In the present study, 7ND protein inhibited the osteoclast differentiation of peripheral blood mononuclear cells without influencing cell proliferation. Furthermore, to evaluate the effects of 7ND protein in vivo, a lipopolysaccharide (LPS)-induced calvarial bone erosion animal model was established. The 7ND protein remarkably attenuated LPS-induced bone resorption, as assessed by micro-computed tomography and histological analysis. Taken together, the present results suggested the feasibility of local delivery of 7ND protein to mitigate osteoclast differentiation and LPS-induced osteolysis, which may represent a potential approach to treat inflammatory bone destruction.