Urothelial Stem Cell Regeneration
Dr. Mysorekar’s 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 physiological outcomes (including bladder pain) thereof.
We are also investigating a role for the sex hormone, estrogen, in modulating susceptibility to UTIs and regulating regeneration following infection/injury. We have developed a murine model of surgical menopause and have shown that estrogen-deficient animals are prone to more aggressive, resistant UTIs and that loss of estrogen is associated with dysregulated urothelial regeneration. Projects include investigating the mechanistic basis for this effect of estrogen on urothelial stem cell niche.