Research Abstract:
My lab is using a multipronged approach to understand the cellular and molecular details of adult stem cell biology of the mammalian urinary bladder. The bladder is lined by a pseudo-stratified transitional urothelium continuously repopulated by a urothelial stem cell (USC). The rate of turnover of the cells in the normal transitional epithelium is slow but continuous: it takes more than 200 days for the progeny of a USC to mature and eventually be shed. Our studies show that following injury to the epithelium, the rate of differentiation and regeneration increases dramatically. To determine the dynamics of tissue regeneration in the adult bladder, we use a model of urothelial injury induced by infection with uropathogenic Escherichia coli (UPEC), the primary causative agent of a common infectious disease in women, urinary tract infections (UTIs). UPEC infection results in rapid sloughing of colonized terminally differentiated superficial cells, disruption of the blood-urine barriers, massive immune cell infiltration, and a remarkable spike in mitotic activity of the basal stem/progenitor cells such that the superficial layer is renewed within days.
Using a blend of confocal and electron microscopy, laser-capture micro-dissection, oligonucleotide arrays, histopathologic analyses, and inducible genetic disruption of key genes in mouse models, we are delineating the cellular mechanisms and molecular regulators that govern the normal rapid, injury-induced regenerative response of otherwise quiescent USCs and to apply what we learn about the normal mechanisms to shed light on the disease processes with abnormal urothelial turnover (e.g. recurrent UTIs, interstitial cystitis/painful bladder syndrome, bladder cancer). We have shown that a key molecular regulator of bladder epithelial renewal is the bone morphogenetic protein 4 (Bmp4) signaling pathway. Projects include using transgenic and knock-out mice to investigate how Bmp4 and other factors coordinate to regulate the complex epithelial developmental pathways that maintain the bladder stem cell niche and its response to injury and consequences thereof.
We also focus on a complication of UTIs, namely, their propensity to recur frequently in a subset of patient population. Clinically, these recurrent UTIs and de novo acute infections are both thought to be due to re-contamination of the urinary tract from the intestinal reservoir. However, we have shown that UPEC establish quiescent reservoirs in endosomal vesicles within the urinary bladder epithelium. UPEC residing within these membrane-bound vesicles can serve as a seed for a new infection concomitant with activation of a round of differentiation in the urothelium. However, little is known about membrane and luminal trafficking events governing the composition of intracellular compartments containing UPEC. We are investigating a role for autophagy in formation and maintenance of these latent infections. Projects in the lab include investigating mechanisms underlying how UPEC can survive within endocytic vesicles and how do they re-emerge from this low-profile lifestyle to cause recurrent urinary tract infections.
A third area of focus in the lab is investigating a role for the sex hormone, estrogen, in modulating susceptibility to UTIs and regulating regeneration following infection/injury. We have demonstrated that bladder colonization by UPEC disrupts protective glycosaminoglycans (GAG)—the “Blood-Urine Barrier. Experimental evidence demonstrates a role for estrogen in the modulation of the GAG layer in human bladders. We have a developed a murine model of surgical menopause and have shown that estrogen-deficient animals are prone to more aggressive, resistant UTIs. Projects include investigating the GAG-estrogen-UTI link that could aid in the development of better therapeutic regimens for treating post-menopausal women.
Selected Publications:
Mysorekar IU , Isaacson-Schmid M, Walker JN, Mills JC, Hultgren SJ. Bone morphogenetic protein 4 signaling regulates epithelial renewal in the urinary tract in response to uropathogenic infection. Cell Host Microbe. 2009 May 8;5(5):463-75.
Hannan TJ, Mysorekar IU, Chen SL, Walker JN, Jones JM, Pinkner JS, Hultgren SJ, Seed PC. LeuX tRNA-dependent and -independent mechanisms of Escherichia coli pathogenesis in acute cystitis. Mol Microbiol. 2008 Jan;67(1):116-28. Epub 2007 Nov 25.
Mysorekar IU , Hultgren SJ. Mechanisms of uropathogenic Escherichia coli persistence and eradication from the urinary tract. Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14170-5. Epub 2006 Sep 12.
Huh WJ, Pan XO, Mysorekar IU, Mills JC. Location, allocation, relocation: isolating adult tissue stem cells in three dimensions. Curr Opin Biotechnol. 2006 Oct;17(5):511-7. Epub 2006 Aug 4.
Mysorekar IU , Mulvey MA, Hultgren SJ, Gordon JI. Molecular regulation of urothelial renewal and host defenses during infection with uropathogenic Escherichia coli. J Biol Chem. 2002 Mar 1;277(9):7412-9. Epub 2001 Dec 13.
Last Updated: 06/18/2009 |