By continuously observing hundreds of individual HSCs

By continuously observing hundreds of individual HSCs and their progeny during differentiation, we can exclude a change in cell-cycle length in HSPCs upon GADD45G expression, which was unexpected, because studies on solid tissue po1 reported a G2/M cell-cycle arrest mediated by GADD45G (Vairapandi et al., 2002). Also, the activation of p38 has been described as a decision point between senescence and apoptosis (Tront et al., 2006). None of these fates were observed in HSCs upon GADD45G expression. Intriguingly, the differentiation kinetics permitted by GADD45G is very fast: HSCs are driven to differentiate into GMPs within 36 hr. During GADD45G-accelerated differentiation, the metastable progenitor stages seem unchanged but are temporally shortened to a minimum. This finding opens a new perspective of our current understanding of sequential differentiation programs in hematopoiesis. Stressed cells with an inability to repair their damage are committed to undergo apoptosis to prevent transformation. Alternatively, the induction of terminal differentiation preserves the integrity of the blood system. This safety mechanism was proposed as a function of the transcription factor BATF in aged HSCs to eliminate damaged HSCs from the system (Wang et al., 2012). The enhanced expression of GADD45G in aged HSCs, and the finding that aged GADD45G-depleted HSCs show an increased self-renewal and accumulation (Wang et al., 2012), may indicate a role of GADD45G in HSC life span control. Further, the epigenetic inactivation of Gadd45g in many malignancies explains the inability of tumor cells to terminally differentiate (Liebermann et al., 2011). Further studies are warranted to utilize the GADD45G-mediated pathway to therapeutically switch misregulated self-renewal in cancer-initiating cells into differentiation.
Experimental Procedures
Author Contributions
Acknowledgments
Introduction Adult stem cells maintain tissue homeostasis by regenerating damaged or lost cells during their lifetime. The decline of the regenerative capacity of stem cells with age compromises tissue integrity and may promote organ failure and diseases of aging (Liu and Rando, 2011). This age-related decline in tissue function is considered to be at the root of overall organismal aging. Whether mechanisms that control aging of stem cells influence organismal longevity is unknown. Identifying regulators of stem cell aging is of major significance for public health because such regulators may contribute to promote healthy aging and be valuable therapeutic targets to combat disorders of aging like cancer and Parkinson’s disease. Hematopoietic stem cells (HSCs) are the most extensively studied model of stem cell aging. Although it has been known for decades that HSC age (Harrison, 1983), and the properties of aged HSCs have been greatly characterized, the mechanisms that govern HSC aging have only begun to be defined. HSC aging leads to a paradoxical increase in the stem cell pool and decline in stem cell function (Morrison et al., 1996; Sudo et al., 2000). One of the prominent modifications of HSC properties with age is their biased differentiation toward myeloid lineage at the expense of their lymphoid potential (Challen et al., 2010; Dykstra et al., 2011; Rossi et al., 2005). These age-associated modulations of the composition of HSC progenies lead to defective adaptive immune response. Similarly, the age-related increased incidence of myeloid malignancies, including acute myeloid leukemias, myelodysplasias, and myeloproliferative neoplasms, may be related to the enhanced generation of myeloid skewed HSC progenies. Aging of HSCs is also associated with increased onset of anemia. Although defects in the DNA damage repair program, increased tumor suppressor function, loss of polarity, and epigenetic deregulation have all been implicated in HSC aging, the mechanisms underpinning the age-associated alterations of HSC lineage specification remain largely unknown (Chambers et al., 2007; Dykstra and de Haan, 2008; Florian et al., 2012; Rossi et al., 2005).