The Rates of Stem Cell Division Determine the Cell Cycle Lengths of Its Lineage

Purna Gadre,Krishanu Ray,Samir Gupta,Debasmita Mazumdar,Nitin Nitsure

doi:10.2139/ssrn.3777474

Abstract

Adult stem cells and their transit-amplifying progeny alter their proliferation rates to maintain tissue homeostasis. To test how the division rates of stem cells and transit-amplifying progeny affect tissue growth and differentiation, we developed a computation strategy that estimates the average cell-cycle lengths (lifespans) of germline stem cells and their progeny from fixed-tissue demography in the Drosophila testis. Analysis of the wild-type data using this method indicated that during the germline transit-amplification, the cellular lifespans extend by nearly 1.3-fold after the first division and shrink by about 2-folds after the second division. Cell-autonomous perturbations of the stem cell lifespan accordingly altered the lifespans of successive transit-amplifying stages. Remarkably, almost 2-fold alterations in the lifespans of stem cells and their immediate daughters did not affect the subsequent differentiation. Together, the results indicate that the early germline division rates can adjust the following division rates and the onset of differentiation.

Highlights

Many adult stem cells produce progenitors, which undergo transit-amplifying (TA) divisions before terminal differentiation
To test how the division rates of stem cells and transit-amplifying progeny affect tissue growth and differentiation, we developed a computation strategy that estimates the average cell-cycle lengths of germline stem cells and their progeny from fixed-tissue demography in the Drosophila testis
The results indicate that the early germline division rates can adjust the following division rates and the onset of differentiation

Summary

Introduction

Many adult stem cells produce progenitors, which undergo transit-amplifying (TA) divisions before terminal differentiation. Previous studies have shown that the TA cells pass through a continuum of transcriptomic states, which sets the time of differentiation – independent of the TA cell cycle rates (Gao et al, 1997; Insco et al, 2009; Cinquin et al, 2010) This conjecture appears inconsistent because coordination of this autonomous differentiation clock with rates of TA divisions is essential for tissue homeostasis, and defects in this process can lead to cancer or other disorders (Clarke and Fuller, 2006; Li and Laterra, 2012; Janssens and Lee, 2014; Zhang and Hsu, 2017). The effect was not fully penetrant (Insco et al, 2009) as several cysts were shown to conclude the TA and meiosis in a wild-type-like manner in the cell cycle perturbed backgrounds This observation suggests that the differentiation clock can adjust to accommodate changes in the rates of TA divisions. We still lack clarity regarding the quantitative limit of this readjustment

Methods

Results

Discussion

Conclusion