The Humphreys Lab

The mission of the Humphreys Lab is to understand the cellular and molecular mechanisms of kidney repair and thereby identify new therapeutic strategies for humans suffering from kidney disease. The work encompasses two main areas: (1) localizing and characterizing adult kidney stem cells and (2) understanding the genetic and epigenetic regulation of epithelial cell dedifferentiaion and proliferation after injury.

Genetic Analysis of Kidney Injury and Repair

Lineage tracing during renal repair. A major current focus of the lab is to investigate the lineage relationships among cell types during renal repair to assess whether adult stem cells contribute to repair. We have developed a method for distinguishing between renal repair by extratubular progenitor cells and renal epithelial cells. We have used a transgenic mouse in which the Six2 promoter drives Cre recombinase in collaboration with the Bonventre and McMahon groups at Harvard. In this strain, Cre is expressed transiently in renal epithelial precursors during development, with no Cre expression in the adult or re-expression after injury. We crossed this Six2-Cre mouse with a reporter strain in which Cre-dependent removal of a stop sequence causes constitutive and heritable expression of a marker gene such as alkaline phosphatase or DsRed. In these mice, renal epithelial cells, from Bowman’s capsule to the distal convoluted tubule, are heritably labeled but extratubular cells such as interstitial cells, remain unlabeled. To test whether unlabeled cells could contribute to the epithelial lineage during renal repair, we perform injury experiments and allow kidneys to recover. By examining repaired tubules for dilution of label vs. retention of label, we are able to assess whether any unlabeled cells contribute to repair of damaged nephrons.

Multipotent Intratubular Stem Cells

Telomerase expression in kidney. In other studies, we are characterizing a transgenic mouse expressing GFP under control of the Telomerase promoter (D. Breault, CHB) to identify adult kidney stem cell populations. Finally, we are generating additional transgenic and knock-in mice that will serve as useful tools in genetic fate-mapping of renal injury. These tools will allow us to distinguish between self-duplication of differentiated epithelial cells versus replacement by a multipotent epithelial progenitor cell. Ultimately, this knowledge will help to focus future efforts at renal regenerative medicine.

Recent Publications