Stem cell proliferation rates are locally regulated in vivo

Stem cell proliferation and differentiation rates in adult tissues are under the influence of systemically-released growth factors. These systemic signals are, however, bypassed in the C. elegans germ line upon accumulation of oocytes, the stem cells' terminally-differentiated progeny, thus highlighting a feedback mechanism that acts to locally control stem cell proliferation rates despite systemic information.

HFSP Long-Term Fellow Patrick Narbonne and colleagues
authored on Tue, 08 December 2015

At any one time, stem cells can either be proliferating to expand in numbers, or differentiating to generate more specialized cells. Surrounding niche cells provide stem cells with key signals that locally promote self-renewal and inhibit differentiation, which only happens when stem cells move away from the niche. When not further stimulated however, stem cells tend to remain inactive or quiescent, and only when they receive growth factors do they begin to proliferate or differentiate. Many of these growth factors that promote stem cell activities are systemically released in multi-cellular organisms, such that they would be expected to equally influence all stem cells across and within tissues. We thus wondered whether two distinct stem cell populations, both located within a single individual, could be independently regulated.

To test this idea, we used the germline stem cells (GSCs) of the nematode Caenorhabditis elegans, which exist as two separate populations that are located at the distal tip of each of two gonad arms. We identified insulin/IGF-1 as a systemically-regulated growth factor that stimulates GSC proliferation in adult animals downstream of nutrient intake. We also noticed that a feedback mechanism senses whether oocytes, a terminally-differentiated progeny of the GSCs, are over-accumulating. When this is the case, we found that GSC proliferation is blocked even when insulin/IGF-1 signalling is normally activated by food intake. Briefly, oocytes are continually produced, ovulated and fertilized during adulthood when sperm is available. If sperm is depleted however, unfertilized oocytes accumulate in each proximal gonad arm and GSC proliferation and differentiation are inhibited, while feeding and insulin/IGF-1 signalling levels remain elevated. By micro-injecting an oil droplet that acted like a diaphragm only in one of the two proximal gonad arms prior to mating with a male, we created the situation in which only one of the two gonad arms was sperm-depleted. While GSCs did not expand in numbers in the contraception-treated gonad arm, they proliferated normally in the untreated arm. Thus, insulin/IGF-1 proliferation-stimulatory effects were specifically blocked in one of the two GSC populations in vivo.

Figure: Localized regulation of stem cell proliferation. In vivo mechanisms monitor for the over-accumulation of terminally-differentiated stem cell progeny and feedback to locally block the proliferation-stimulatory effects of growth factors specifically on their source stem cells.

These results are important because they show that the effects of systemically-released growth factors can be locally overridden by other signals in vivo. A better understanding of how such localized inhibition of cell proliferation is accomplished in vivo may help to design novel strategies to treat proliferative diseases, including cancer, in a similarly localized manner. This would potentially alleviate many of the side effects of current anti-proliferative compounds and could allow for the use of more potent doses.

Reference

DAF-18/PTEN locally antagonizes insulin signalling to couple germline stem cell proliferation to oocyte needs in C. elegans, Narbonne, P., Maddox, P.S., Labbé, J-C. Development 2015 : doi: 10.1242/dev.130252.

Pubmed link