FoxO is a critical regulator of stem cell maintenance in immortal Hydra

Abstract

Hydra ’s unlimited life span has long attracted attention from natural scientists. The reason for that phenomenon is the indefinite self-renewal capacity of its stem cells. The underlying molecular mechanisms have yet to be explored. Here, by comparing the transcriptomes of Hydra ’s stem cells followed by functional analysis using transgenic polyps, we identified the transcription factor forkhead box O (FoxO) as one of the critical drivers of this continuous self-renewal. foxO overexpression increased interstitial stem cell and progenitor cell proliferation and activated stem cell genes in terminally differentiated somatic cells. foxO down-regulation led to an increase in the number of terminally differentiated cells, resulting in a drastically reduced population growth rate. In addition, it caused down-regulation of stem cell genes and antimicrobial peptide (AMP) expression. These findings contribute to a molecular understanding of Hydra ’s immortality, indicate an evolutionarily conserved role of FoxO in controlling longevity from Hydra to humans, and have implications for understanding cellular aging.

Living long and ageing well: is epigenomics the missing link between nature and nurture?

“…Long-living hydras seem to live for ever since they can reproduce themselves by using new stem cells. In searching out a reason for this remarkable finding, scientists found that the FoxO gene family was important for stem cell production and when inactivated, the hydra showed compromised immune function and early death (Boehm et al 2012). All organisms have a version of the FOXO gene or family of genes which is related to the insulin pathway and variation in single genes can result in substantial differences in life-span.…”

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

“…Three stem cell lineages allow this continuous self‐renewal: ectodermal and endodermal epitheliomuscular stem cells and interstitial stem cells (Bosch, 2009; Bosch et al ., 2010). The search for transcriptome‐specific signatures enabling the regulation of self‐renewal and differentiation showed that FoxO is highly expressed in the three stem cell lineages of Hydra (Boehm et al ., 2012). The overexpression of FoxO in the multipotent interstitial stem cell lineages increases stem cell and progenitor cell proliferation and activates expression of stem cell genes in terminally differentiated somatic cells (Boehm et al ., 2012).…”

“…The search for transcriptome‐specific signatures enabling the regulation of self‐renewal and differentiation showed that FoxO is highly expressed in the three stem cell lineages of Hydra (Boehm et al ., 2012). The overexpression of FoxO in the multipotent interstitial stem cell lineages increases stem cell and progenitor cell proliferation and activates expression of stem cell genes in terminally differentiated somatic cells (Boehm et al ., 2012). Conversely, silencing FoxO in epithelial cells increased the number of terminally differentiated cells (Boehm et al ., 2012) Altogether, these results suggest a key role for FoxO in Hydra 's apparent biological immortality, specifically affecting its continuous self‐renewal capacity (Bellantuono et al ., 2015).…”

“…The overexpression of FoxO in the multipotent interstitial stem cell lineages increases stem cell and progenitor cell proliferation and activates expression of stem cell genes in terminally differentiated somatic cells (Boehm et al ., 2012). Conversely, silencing FoxO in epithelial cells increased the number of terminally differentiated cells (Boehm et al ., 2012) Altogether, these results suggest a key role for FoxO in Hydra 's apparent biological immortality, specifically affecting its continuous self‐renewal capacity (Bellantuono et al ., 2015). In a recent essay, Schaible and Sussman hypothesized that whereas FoxO is exclusively devoted to life‐prolonging cell renewal in Hydra , the evolutionary diversification of FoxO functions in multicellular eukaryotes that manifest aging resulted in a dilution of FoxO's rejuvenating capacity (Schaible & Sussman, 2013).…”

Aging and Potential for Self-Renewal: <b><i>Hydra</i></b> Living in the Age of Aging - A Mini-Review

“…Another study showed that FOXO might be involved in inducing the apoptosis of Hydra epithelial stem cells, a conserved function which may play a key role in maintaining body proportions [53]. Boehm et al [54] detected a clear relationship between FOXO expression and stem cell homeostasis and maintenance, which influence stem cell proliferation and differentiation rates (from stem cells to somatic cells like head or foot cells). Besides FOXO, other genes like Oct4, a class5 POU domain protein, and the transcription factors of the Myc family [both reviewed in [55]], may play a significant role in controlling the dynamics of stem cell proliferation and are therefore suspected to play a major role in the longevity pattern of Hydra .…”