**6. Acknowledgments**

I would like to thank to Drs. Atsushi Hirao, Makoto Suematsu, Nobuhito Goda, Tomoyoshi Soga, and Randall S. Johnson for providing thoughtful insights and collaborations for this review. Most of our work on hypoxia in HSCs was performed in Dr. Toshio Suda's laboratory at the Keio University School of Medicine, Tokyo, Japan under his careful management. I would like to acknowledge my deep appreciation of fruitful discussions with the previous and current members of the Stem Cell Metabolism group of the Suda lab, especially Dr. Hirono Iriuchishia, Dr. Chiharu Kobayashi, Dr. Hiroshi Kobayashi, Dr. June-Won Cheong, Dr. Ayako Ishizu, and Ms. Wakako Yamada. Also, I would like to thank Ms. Tomoko Muraki and Ms. Takako Hirose for the preparation of this manuscript. K.T. is supported by the Global COE Program for Human Metabolomic Systems Biology and for Stem Cell Medicine of the Japan Society for Promotion of Science, and also in part by a Ministry of Education, Culture, Sports, Science and Technology (MEXT) Grant-in-Aid for Young Scientists (A), a MEXT Grant-in-Aid for Scientific Research (A), and a MEXT Grantin-Aid for Scientific Research on Innovative Areas. The author dedicates this paper to the memory of Masako Takubo, who passed away October 9, 2011.

#### **7. References**

142 Advances in Hematopoietic Stem Cell Research

HSCs, which actively proliferate in hypoxic conditions, because HIF-1 may support HSC proliferation in that stage. In addition, HIF-1 protein has been reported to inhibit Wnt/ catenin activity in cancer cells (Kaidi A et al, 2007), suggesting that the interaction of the HIF-1 and Wnt/-catenin pathway in stem/progenitor cells may differ from that of more

In this chapter, I have summarized our current knowledge regarding the hypoxia response and oxygen metabolism in HSCs at the BM niche. These studies open novel fields in stem cell biology. The invisible niche factor, oxygen, is usually essential because mitochondria utilize it for the energy production. However, molecular oxygen is a source of ROS during mitochondrial metabolism. Because an excessive dose of ROS can be damaging to HSC, escape from oxygen (in the hypoxic niche) is a reasonable strategy for the long-term maintenance of HSCs *in vivo*. Adult HSCs are quiescent and contain few mitochondria, whereas hematopoietic progenitor cells actively proliferate and contain many mitochondria. Thus, stem cells and progenitors have distinct metabolic states, and the transition from stem to progenitor cell may correspond to a critical metabolic change, namely from glycolysis to oxidative phosphorylation. Slow cell cycling or long-term quiescence is common in adult tissue stem cells. Dormancy in the cell cycle may be a crucial mechanism for the stress

Further investigation of oxygen metabolism in tissue stem cells will result in more effective maintenance, expansion, and manipulation of various somatic stem cells *ex vivo* and *in vivo*, maximizing the potential of therapeutic strategies using stem cells in regenerative medicine. Also, an understanding of oxygen homeostasis in HSCs is essential for understanding senescence at the stem cell level as well as therapeutic

I would like to thank to Drs. Atsushi Hirao, Makoto Suematsu, Nobuhito Goda, Tomoyoshi Soga, and Randall S. Johnson for providing thoughtful insights and collaborations for this review. Most of our work on hypoxia in HSCs was performed in Dr. Toshio Suda's laboratory at the Keio University School of Medicine, Tokyo, Japan under his careful management. I would like to acknowledge my deep appreciation of fruitful discussions with the previous and current members of the Stem Cell Metabolism group of the Suda lab, especially Dr. Hirono Iriuchishia, Dr. Chiharu Kobayashi, Dr. Hiroshi Kobayashi, Dr. June-Won Cheong, Dr. Ayako Ishizu, and Ms. Wakako Yamada. Also, I would like to thank Ms. Tomoko Muraki and Ms. Takako Hirose for the preparation of this manuscript. K.T. is supported by the Global COE Program for Human Metabolomic Systems Biology and for Stem Cell Medicine of the Japan Society for Promotion of Science, and also in part by a Ministry of Education, Culture, Sports, Science and Technology (MEXT) Grant-in-Aid for Young Scientists (A), a MEXT Grant-in-Aid for Scientific Research (A), and a MEXT Grantin-Aid for Scientific Research on Innovative Areas. The author dedicates this paper to the

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**6. Acknowledgments** 

**5. Conclusion** 


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**8** 

*USA* 

**Skeletogenesis and the Hematopoietic Niche** 

The reciprocal regulation of the skeletal and the immune systems has been clinically appreciated for years. In particular, factors produced by immune cells during homeostasis and activation markedly affect the skeleton, which in turn affects the marrow niche environments (as reviewed in (Compston 2002). This relationship also extends to an interdependence between bone and hematopoiesis during immune cell development, however the critical cell types and extracellular matrix components involved in establishing and maintaining hematopoietic niches within the bone marrow are only recently beginning to be defined. Indeed, some immuno-osseous disorders with hematopoietic defects such as bone marrow failure and immune dysfunction, as well as certain cancers, may result from a defective hematopoietic niche (Spranger et al. 1991; Kuijpers et al. 2004; Hermanns et al. 2005; Walkley et al. 2007; Walkley et al. 2007; Raaijmakers et al. 2010). Likewise during aging, a progressive decline in cell replacement and repair manifests in both the skeletal and hematopoietic systems with reduced bone mass and diminished blood cell formation respectively (as reviewed in (Rossi et al. 2008) and (Gruver et al. 2007). Further, this altered hematopoiesis due to aging leads to deficient immune function and increased incidence of malignancies (Rossi et al. 2005; Janzen et al. 2006; Mayack et al. 2010). Thus, the dynamic relationship between skeletal and hematopoietic maintenance throughout life suggests that these clinical outcomes may ensue from cell signaling deficiencies or from defects in the structural environment supporting hematopoiesis. This chapter provides an overview of our current understanding of how hematopoietic niches may be established, how they promote

hematopoiesis, and how the skeletal status may modulate niche function.

The vertebrate skeleton develops by one of two essential processes, endochondral (EO) and intramembranous (IO) ossification mechanisms (as reviewed in (Chan, D. and Jacenko 1998). The direct differentiation of ectomesenchymal cells to osteoblasts in IO represents the rudimentary mechanism through which many skull bones and all periosteal bones form. The IO-derived bone is referred to as "dense", "compact" or "cortical", and as the names imply, is a solid bone with primary functions relating to weight bearing and protection (**Fig. 1C**). In contrast, EO relies on the generation of a cartilaginous skeletal blueprint that is gradually replaced by a "trabecular", "spongy", "cancellous" bone and a marrow capable of sustaining hematopoiesis (Chan, D. and Jacenko 1998; Mackie et al. 2008) (**Fig. 1C**). This replacement mechanism of EO is responsible for the formation of the vertebrate axial and appendicular skeleton, as well as certain cranial bones (Jacenko et al. 1991; Chan, D. and Jacenko 1998).

**2. Coordinate skeletal and hematopoietic development** 

**1. Introduction** 

Elizabeth Sweeney and Olena Jacenko

*University of Pennsylvania* 

Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, Lagutina I, Grosveld GC, Osawa M, Nakauchi H, Sorrentino BP. (2001) The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. *Nat Med.* Sep;7(9):1028-34.
