**10. Acknowledgements**

We thank Amanda Maia and André Mencalha for the excellent figures design.

#### **11. References**


A particularly exciting development in basic stem cell research in the past few years is the discovery of novel functions of cell cycle regulators in controlling the asymmetry of stem cell division, as timely reviewed by Chia et al (2008). For example, the *cdc2/cdk1* level controls whether a neural or muscle progenitor undergoes symmetric or asymmetric division. In neuroblasts, high levels of CDK1 during mitosis are required for the asymmetric localization of apical and basal protein complexes. In addition, Aurora and Polo kinases act as tumor suppressors in neuroblasts by preventing excess self-renewal, implicating the function of asymmetric division in restricting over-proliferation. The mutations of these two kinase genes affect the asymmetric localization of aPKC, Numb, Partner of Numb, and Notch, causing symmetric division to generate two daughter neuroblasts. In addition, anaphase-promoting complex/cyclosome is also required for the localization of Miranda and its cargo proteins (Prospero, Brain Tumor, and Staufen). More surprisingly, even cyclin

Interestingly in epidermal progenitors the decision of choosing between symmetric cell division or asymmetric cell decision is tightly regulated. Two control points have been indentified: expression of Inscutable and recruitment of NuMA to the apical cell cortex. Moreover in embryonic lung distal epithelium Eya1 protein regulates cell polarity, spindle orientation and the localization of Numb, which inhibits Notch signaling with the

In the last ten years a body of evidence has accumulated on the hematopoietic stem cell niches and the mechanisms by which they regulate HSCs homeostasis. However many questions remain to be addressed. What we can speculate with today data is that in the endosteal niche dissimilar stages of differentiating osteoblasts provides diverse signals. These signals induce a quiescent or a self-renewal fate. However after leaving quiescence HSCs are prone to accumulate mutations that will lead to senescence. To prevent HSCs exhaustion mechanisms to enhance survival are also induced. Several of these additional signals come from the osteoblasts but also from other cells from microenvironment as stromal cells and endothelial cells. This is specially visualized in the decision of a symmetric or asymmetric division. From the control of all these interconnected pathways depends a

We thank Amanda Maia and André Mencalha for the excellent figures design.

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**9. Conclusion** 

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**2** 

*Japan* 

**Regulation of Hematopoietic Stem Cell Fate:** 

Hematopoietic stem cells (HSCs) are probably the most extensively characterized somatic stem cells and are the only stem cells that have been clinically used to treat diseases such as leukemia, germ cell tumors, and congenital immunodeficiencies. Because of their capacity for self-renewal and their ability to differentiate into different lineages, HSCs are able to continually replenish the cells that make up the hematopoietic system (Kondo et al., 2003). Decades of intensive study using multicolor cell sorting techniques have allowed investigators to identify these cells within a small population in the mouse bone marrow (BM) (i.e., CD34low/-, Kit+ Sca-1+ lineage marker-negative cells: CD34low/- KSL) and thereby allow the prospective isolation of nearly-homogenous HSC populations for further

Under steady-state conditions, the majority of HSCs are maintained in a quiescent state in which they divide infrequently to produce proliferative progenitors that eventually give rise to the mature hematopoietic cells that sustain blood homeostasis (Cheshier et al., 1999). However, in response to external stresses such as bleeding, myeloablative chemotherapy and total body irradiation, HSCs proliferate extensively to produce very high numbers of primitive progenitor cells, thereby enabling rapid hematological regeneration (Randall et al., 1997). Once recovery from myelosuppression has been achieved, the activated HSCs return to a quiescent state via a number of negative feedback mechanisms (Venezia et al., 2004). The cell fate decisions (including life and death, self-renewal and differentiation) of HSCs are important processes that regulate the number and lifespan of the HSC pool within a host. Defects in these processes may contribute to hematopoietic failures and to the

Understanding the molecular mechanisms underlying HSC regulation is of great importance to basic stem cell biology and for the development of HSCs for use in various clinical applications. Information regarding the regulation of HSC fate has been gained using conventional experimental approaches such as gene deletion, gene overexpression, and the direct stimulation of HSCs with cytokines. Although many studies have elucidated the factors controlling HSC fate using these methods, they can occasionally be misleading

**1. Introduction** 

characterization (Osawa et al., 1996).

development of hematologic malignancies.

**Self-Renewal, Quiescence and Survival** 

*Department of Internal Medicine, Faculty of Medicine, Saga University* 

*1Division of Hematology, Respiratory Medicine and Oncology,* 

*2Department of Transfusion Medicine, Saga University Hospital* 

Yasushi Kubota1,2 and Shinya Kimura1

