Abstract
Anemia poses a life-threatening risk to individuals with chronic kidney diseases (CKDs). Insufficient production of erythropoietin (EPO) from the injured kidney is the major reason for anemia, while lack of EPO would further aggravate the kidney injury and make a "vicious cycle." In this study, we dissected the change of endogenous EPO signaling in the injured kidney by spatial transcriptomic analysis and validated the dual beneficial effects of local recombinant EPO administration on both anemia correction and kidney protection. Next, we constructed an injury-responsive EPO-producing (iREP) element to sense the kidney damage signal and drive the synthesis and secretion of native EPO. After intrarenal implantation of iREP-engineered HEK-293T embryonic kidney cells, the mouse kidney would automatically produce more EPO when sensing injury signal, which in turn enhanced red blood cell count and protected the kidney from further injury. Moreover, we cloned urine-derived SOX9+ epithelial cells (USCs) from healthy donors. The USCs can be transplanted into mouse kidneys, which makes them an alternative candidate cell for iREP engineering. Altogether, the current work proposed a potential approach based on an engineered "smart" cell to treat CKDs.