Establishing a Model of Organ regeneration in the Adult Mammal: Age Dependence and the Utility of Non-Invasive Imaging

Abstract

Although models of regenerative biology in lower vertebrates (e.g., salamanders, axolotls) have been utilized to study in vivo organ regeneration, there are far fewer opportunities in the adult mammal. One obscure example of mammalian organ regeneration is the urinary bladder, where the regenerative capacities have been known to urologists for some time. Despite anecdotal evidence for de novo growth of the, very few studies have examined the extent of bladder regeneration using animal models. Understanding caveats and strengths of bladder regeneration per se would undoubtedly enhance the field of urological tissue engineering. To this end, the goal of this effort was to characterize the extent of bladder regeneration, with specific emphasis on restoration of function. Furthermore, the impact of age on bladder regeneration, and the prognostic value of non-invasive imaging were evaluated. Removal of a large portion of the urinary bladder (subtotal cystectomy; STC) in adult rats initiated a proliferative response that gave rise to normal bladder wall architecture, including nerves, vessels, urothelium, and smooth muscle. Despite subtle differences in shape and contractility, bladders displayed a normal low pressure, high capacity function, and were able to empty completely 8 weeks after cystectomy. Computed tomography imaging corroborated this increase in bladder volume, and moreover was able to predict a rate of bladder growth that resulted in normal function. Magnetic Resonance Imaging revealed a progressive thickening of the bladder wall, which also conveyed information about bladder wall composition. When STC was performed in moderately aged rats, capacity failed to return to normal values, with further compromised smooth muscle contractility which was accompanied by a delayed proliferative response. Most strikingly, evidence of chronic kidney damage was found. This failure to recover the high-volume function of the bladder was not reversed by local administration of adipose derived stem cells at the time of STC. These studies establish an age-dependent model of mammalian organ regeneration that may be utilized to identify molecular regulators of (un)successful regeneration. While targetable pathways specific to bladder tissue engineering may be leveraged with this model, molecular differences may also lead to an understanding of impaired regenerative capacities due to aging.