Qais Al-Awqati, M.D. Ch.B.
Professor of Physiology & Cellular Biophysics
Epithelial differentiation and protein targeting; molecular mechanisms of organogenesis of the kidney.
Stem Cells in the Kidney
Stem cells are characterized by low cycling time and a standard procedure in the field is to apply BrdU in a short pulse to an animal and to follow it by a long term chase. Cells that retain the label (Label-retaining cells or LRCs) are considered to be stem cells. We found that in the adult kidney, these stem cells are concentrated in the papilla and located mostly outside the renal tubule. When the kidneys were subjected to unilateral ischemia followed by re-perfusion, we found that these LRCs migrated out of their niche in the papilla and started to rapidly divide. Purification of these cells led to identification of a gene that is expressed in them but in no other cell in the kidney. To provide definitive evidence for the existence of stem we need to produce a “lineage marker”. We generated a mouse that expresses the Cre recombinase (Cre:ERT2) under a control of its promoter and bred this mouse to a reporter strain such that these cells express a fluorescent protein but only when a drug (tamoxifen) induces the Cre expression. We found that these marked cells exist in the papilla as clusters of cells but are present as single cells in every nephron segment. Ischemic injury led to proliferation and migration of these cells to the site of injury followed by incorporation into the injured nephron segments. Thus these cells are bona fide stem cells of the adult kidney.
Response of the Kidney to Acidosis
Over the past two decades we have shown that the collecting tubule of the nephron contains two types of intercalated cells, α-intercalated cells secrete acid while β-intercalated cells secrete HCO3. We have shown that the β-IC converts to the α-IC form when the animal is fed an acid diet. We showed that this conversion is a process of differentiation induced by the deposition of an extracellular matrix protein called hensin/DMBT1. Deletion of hensin results in a complete blockade of the conversion. We recently discovered that the proximate signal by which the cell senses a change in extracellular pH is secretion of the chemokine SDF1. We are presently investigating the mechanism by which SDF1 and its receptor CXCR4 mediate this effect.
Branching Morphogenesis during kidney development
The kidneys develop when an epithelial outgrowth of the Wolffian duct (the ureteric bud) invades the metanephric mesenchyme causing it to convert to the epithelial nephron. The epithelia then send signals that induce another round of branching. Hence, the branches of the tree eventually determine the number of nephrons. We began a new project in which we are attempting to map the entire branching tree during kidney development and to identify the entire map of the branching tree and we are studying the effect of specific gene deletions on the pattern of branching.
Oliver JA, Maarouf O, Cheema FH, Liu C, Zhang QY, Kraus C, Zeeshan Afzal M, Firdous M, Klinakis A, Efstratiadis A, Al-Awqati Q. SDF-1 activates papillary label-retaining cells during kidney repair from injury. Am J Physiol Renal Physiol. 302(11):F1362-73. 2012.
Al-Awqati Q, Gao XB. Differentiation of intercalated cells in the kidney. Physiology (Bethesda). 2011 Aug;26(4):266-72
Gao X, Eladari D, Leviel F, Tew BY, Miró-Julià C, Cheema FH, Miller L, Nelson R, Paunescu TG, McKee M, Brown D, Al-Awqati Q., Deletion of hensin/DMBT1 blocks conversion of beta- to alpha-intercalated cells and induces distal renal tubular acidosis. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21872-7.
Al-Awqati,Q. Oliver, JA. 2006 The kidney papilla is a stem cells niche. Stem Cell Rev.2:181-4.
Oliver, J.A., Maarouf O., Cheema, F.S., and Al-Awqati Q., The renal papilla is the "niche" for adult kidney stem cells. J. Clin. Invest. 114, 795-804. 2004