Author's Department/Program

Biology and Biomedical Sciences: Developmental, Regenerative and Stem Cell Biology

Language

English (en)

Date of Award

Summer 9-1-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Raphael Kopan

Abstract

Nephrons, the basic functional units of the kidney, are built from an embryonic progenitor population called the cap mesenchyme (CM). Although stem-like in many aspects, these progenitors exhaust before or shortly after birth when nephron numbers reach a species appropriate limit termed "nephron endowment" . The actual number of nephrons varies greatly between individuals, and low nephron numbers have been linked to hypertension and other renal diseases. However, the mechanisms that lead to the depletion of CM cells remain elusive.

We hypothesized that cell intrinsic changes of the CM actively regulate the lifespan of CM cells. To test this hypothesis, we established a new assay system where the ability of CM to remain as nephron progenitors could be evaluated upon transplantation into an endogenous CM niche. By co-transplanting nephron progenitors isolated from different embryonic stages, we discovered that young and old progenitors display differential proliferation rate, adhesion properties and their ability to remain in the niche is inversely correlated with age. Importantly, an unbiased transcriptome profiling of nephron progenitors at the single cell level revealed distinct transcriptional signature of different age groups, further supporting an intrinsic difference. Interestingly, although most old progenitors exit the niche sooner than young progenitors, a few of them could remain in the niche beyond their endogenous lifespan when completely surrounded by young neighbors, indicating that age-related changes are possibly reversible.

Together, these data is consistent with a gradual intrinsic change in the CM preceding the cessation of nephrogenesis. Manipulating age-related changes may open the door to increasing nephron endowment in at-risk individuals.

Comments

This work is not available online per the author’s request. For access information, please contact digital@wumail.wustl.edu or visit http://digital.wustl.edu/publish/etd-search.html.

Permanent URL: http://dx.doi.org/10.7936/K76W982P

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