F A C U L T Y P R O F I L E
AL-AWQATI, QAIS M.D, CH.B
Epithelial differentiation and protein targeting; molecular mechanisms of organogenesis of the kidney.
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Epithelia are the first differentiated cells to appear during embryonic development forming the trophectoderm of the blastocyst. They originate from non-polarized cells, but even a superficial examination of tissue sections shows that each organ contains several types of polarized epithelia. In particular, simple epithelia are divided into squamous, cuboidal and columnar types. The mechanism by which these types are generated is not known. We proposed that epithelial development starts by conversion of non-epithelial cell to a protoepithelium; this "generic" epithelium then converts into the more mature types by terminal differentiation such as squamous or columnar types. We discovered that a new extracellular matrix protein hensin induced terminal differentiation to a columnar phenotype. We recently knocked out hensin and found that embryos die at the first stage of columnarization, in the egg cylinder stage. At this stage, the first columnar epithelium is responsible for induction of the anterior-posterior axis. We cultured ES cells on hensin-coated filters and found that they differentiated to columnar epithelia while culture on laminin caused squamous epithelia. ES cells seeded on collagen IV and fibronectin did not differentiate.
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 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. Interestingly, they are present mostly under the urinary epithelium of the papilla. Clonal analysis of these cells show that they can differentiate into epithelial, smooth muscle and endothelial cells. When injected into the kidney purified papillary cells were able to incorporate into various tubule segments. When the kidneys were subjected to unilateral ischemia followed by re-perfusion, we found that these label retaining cells migrated out of their niche in the papilla and started to rapidly divide. We suggest that these cells are used to repair the damaged epithelial cells of the nephron after ischemia. Present studies aim at isolation of these cells and determination of their expression profiles.
Vijayakumar S., H. Erdjument-Bromage, P. Tempst, and Q. Al-Awqati. Assembly and function of hensin in the extracellular matrix of intercalated cells is mediated by integrins. J. Amer. Soc. Nephrol 19:1079-91. 2008
Al-Awqati, Q. 2008. The 2007 Homer W. Smith award Lecture: Control of terminal differentiation in epithelia. J Am Soc Nephrol. 19:443-9.
Al-Awqati, Q. Oliver, JA. 2006 The kidney papilla is a stem cells niche.
Stem Cell Rev.2:181-4.
Vijayakumar S, Takito J, Gao XB Schwartz GJ and Al-Awqati Q. 2006. Differentiation of Columnar Epithelia: The Hensin Pathway. J. Cell Science. 119:4797-4801.
Schwaderer,AL, Vijayakumar, S, Al-Awqati,Q and Schwartz,GJ. 2006. Galectin-3 Expression is induced in renal b-Intercalated Cells during Metabolic Acidosis. . Amer. J. Physiol. (Renal Physiol. 290:F148-58.
Watanabe, S, Tsuruoka,S, Vijayakumar,S, Fischer,G Zhang,Y Fujimura,A., Al-Awqati, Q., and Schwartz,GJ. 2005. Cyclosporin produces distal Renal Tubular Acidosis by blocking peptidyl cis-trans prolyl isomerase activity of cyclophilin. Amer. J. Physiol. (Renal Physiol.) 288:F40-F47.
Chen, L., and Al-Awqati Q. 2005. Segmental expression of Notch and Hairy genes in nephrogenesis. Am J Physiol Renal Physiol. 288(5):F939-52.
Oliver, J.A., Maarouf O., Cheema, F.S., and Al-Awqati Q. 2004. The renal papilla is the "niche" for adult kidney stem cells. J. Clin. Invest. 114, 795-804.
Takito, J., and Al-Awqati Q. 2004. Conversion of ES cells to Columnar Epithelia by Hensin and Squamous Epithelia by Laminin. J. Cell Biol. 116, 1093-1102.
Al-Awqati, Q. 2003. Terminal Differentiation of Intercalated Cells; the role of Hensin. Annual Review of Physiology 65, 567-583.