Epigenetic Reprogramming in IC/PBS

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Editorial - Epigenetic Reprogramming: A Possible Etiological Factor in Bladder Pain Syndrome/Interstitial Cystitis?

Written by Philip M. Hanno, MD
Wednesday, 18 March 2009
BERKELEY, CA (UroToday.com)

Epigenetic Reprogramming May Have Role in Bladder Pain Syndrome/Interstitial Cystitis

How is it possible that chronic symptoms similar to those characteristic of bacterial cystitis persist for years in patients with BPS/IC in whom no infectious agent is detected at the time of diagnosis? What are the mechanisms by which noxious stimuli in the bladder lumen may trigger abnormal function of the muscle and nerve tissue underlying the uroepithelium, causing pain and the persistent urge to void? These are questions posed by Ada Elgavish from Birmingham, Alabama in her fascinating review of epigenetic reprogramming as a possible etiological factor in BPS/IC.

She notes evidence of mechanisms by which noxious stimuli in the bladder may trigger abnormal function of the epithelium as well as the muscle and nerve tissues underlying it. Recent studies suggest that the uroepithelium is intimately associated with the nervous system. Under normal conditions the uroepithelium receives sensory inputs including mechanical stimuli, soluble factors in the urine or neurotransmitters via a wealth of receptors and ion channels including the TRP channel superfamily. Sensory inputs can stimulate the release of sensory outputs produced by the uroepithelium including growth factors and neurotransmitters. It is possible that pain experienced long after infection and bladder inflammation resolve may be related to neuroplastic changes induced by nerve growth factor, whose expression was triggered by an acute insult.

Elgavish postulates that transient but severe environmental cues such as noxious stimuli associated with infection and inflammation may trigger epigenetic reprogramming of a subpopulation of stem cells in the urothelium, providing a possible mechanism for transdifferentiation processes. Inflammatory mediators may act via epigenetic mechanisms on stem cells in the basal layer of the urothelium, inducing NFkB activation and, finally, their epigenetic reprogramming. During recovery following the insult, the urothelium is repopulated with progeny of the epigenetically modified stem cells, resulting in an activated urothelium that mimics the perpetual response to inflammatory mediators and signals to mast cells and the underlying neural plexus. The succession of events may lead to epithelial dysfunction, mast cell activation, and neurogenic inflammation characteristic of BPS/IC.

This theory provides a possible explanation for the persistence of an altered state in the absence of the initial signal. It also provides a promising, new experimental paradigm for exploring the etiology of BPS/IC.

Elgavish A.


J Urol. 2009 Mar;181(3):980-4
10.1016/j.juro.2008.10.145

PubMed Abstract
PMID: 19150095