**2. Composition of the mouse hematopoietic system**

Hematopoietic stem cells often replenish the whole blood system throughout the life span of the body and maintain hematopoietic homeostasis. In Till and McCulloch's landmark work [22, 23, 26], they utilized colony-forming unit-spleen (CFU-S) assay to identify functional HSCs even while these HSCs were a mixed

**81**

**Figure 1.**

*CD34<sup>−</sup>CD135<sup>−</sup>CD150+*

*multipotent progenitors (MPPs, CD34+*

*Space Radiation-Induced Hematopoietic Stem Cell Injury*

population with different proliferating and self-renewal abilities. This pioneering research not only provided strong evidence to show in vivo HSC existence but also stimulated many investigators to define and isolate HSCs and characterize their

Scal-1, which are therefore named lineage negative (Lin-), c-Kit+

CD48<sup>−</sup>LSK cells. MPPs are CD150+/−CD48+

LSK cells (**Figure 1**). HPCs express c-Kit, but not Sca-1, and are termed Lin<sup>−</sup>c-

used different strategies to identify HSCs. Combination of CD34 or ThyloFlk-2<sup>−</sup> with LSK surface markers was used to isolate HSCs, named as CD34<sup>−</sup>LSK and Thy1loFlk-2<sup>−</sup>LSK cells, respectively [26]. Trumpp's group combined CD34, CD135, CD150, CD48, and LSK markers to further differentiate HSC into long-term

expression of ATP-binding protein like ABCG2 and can efflux DNA-binding dye Hoechst 33342. The Hoechst-effluxing side population (SP) cells were therefore used to indicate HSC population in the case of some circumstances [28], such as

It is well-documented that the hematopoietic system is organized in a hierarchical manner (**Figure 1**). The rare long-term HSCs are located at the top of the hierarchy and have the capacity to self-renew, proliferate, and differentiate into various lineages of mature blood cells though immature MPPs and HPCs [29]. The most important feature of HSCs is quiescent to maintain their self-renewal ability

*Composition of mouse hematopoietic system. Long-term hematopoietic stem cell (LT-HSCs,* 

*CD150+/<sup>−</sup>CD48+*

*different progenitors, such as common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs) and their progeny megakaryocyte/erythroid progenitors (MEPs), and granulocyte/monocyte progenitors (GMPs).* 

*CD135+*

*proliferate, and differentiate into short-term HSCs (ST-HSC, CD34+*

*Progenitors can proliferate different lineages of mature blood cells.*

*CD48<sup>−</sup>LSK cells) is located at the top of the hierarchy and has the ability to self-renew,* 

*CD135<sup>−</sup>CD150+*

*CD48<sup>−</sup>LSK cells) and* 

*LSK cells), which can further differentiate into* 

In the decades since Till and McCulloch's study [22, 23, 26], multiple cell surface markers have been used to separate HSCs from other populations. For example, lineage cell surface markers, such as Ter119, CD4, CD8, B220, Gr-1, Mac-1, and NK1.1, are not detected neither in mouse multipotent progenitors (MPPs) nor in hematopoietic progenitor cells (HPCs). Both HSCs and MPPs express c-Kit and

Sca-1<sup>−</sup>. In 2005, Kiel et al. further utilized CD150 and CD48 surface markers to distinguish HSCs and MPPs [27]. HSCs express CD150, but not CD48, and termed

CD48<sup>−</sup>LSK cells) and short-term HSCs (CD34+

CD48<sup>−</sup>LSK cells). In addition, HSCs have a feature with highly

, and Sca-1<sup>+</sup>

LSK cells. Investigators also

as

*DOI: http://dx.doi.org/10.5772/intechopen.88914*

properties in mice and humans.

HSCs (CD34<sup>−</sup>CD135<sup>−</sup>CD150+

5FU and radiotherapeutic stress conditions.

Kit<sup>+</sup>

CD150+

CD135<sup>−</sup>CD150+

*Beyond LEO - Human Health Issues for Deep Space Exploration*

risk to astronauts' health during a long-term space mission [9, 12].

high-linear energy transfer that might heavily contribute to GCR in space [9]. There are many different components including ions, hydrogen, helium, and so on in spacecraft [10]. Based on measurements in the Mars Science Laboratory from 2011 to 2012, the irradiation dose of GCR in the spaceflight was approximately 481 ± 80 μGy per day [11]. For a 600- to 900-day Mars mission, the total radiation doses from GCR reside between 0.33 and 0.49 Gy. Therefore, the total radiation dose from SPE and GCR will reach to 1.0 Gy or above. Although doses and dose rates of space radiation are low, it will still result in space dose accumulation in the body and high

Radiation-induced tissue damage in the body has long been understood since Wilhelm Röntgen discovered X-ray in 1895 [13]. Hematopoietic and gastrointestinal systems have been shown to be the two most sensitive compartments of the body to radiation. It has been well-documented that radiation (including space radiation) also induces dysfunction of the brain, manifesting as behavioral and cognitive disabilities [14, 15]. The detrimental effects of X-ray radiation in the body were firstly reported by Warren and Whipple [16] and Shouse et al. [13]. They reported that exposing dogs to high doses of X-rays resulted in death from severe hematopoietic suppression and damage. The detrimental effects of radiation on human health were heavily realized after the use of the first atomic bombs in 1945. Many people in Hiroshima and Nagasaki who survived the initial bomb blast later died from radiation exposure in the event. Long-term toxic impacts of the atomic bomb on humans were observed as well, such as the high risk of hematopoietic malignancies. Further studies proved that hematopoietic failure was one of the primary reasons in radiation-induced death when animals experienced a moderate to high dose of total-body irradiation. This is supported by a study in the 1940s showing that shielding the spleen or one entire hind leg with lead or transplantation of splenocytes protected mice from the lethal effect of irradiation [17]. The importance of hematopoietic cells under radiation was also supported by studies showing that intravenous infusions of bone marrow (BM) cell suspensions protected mice from the effects of radiation [95]. Initially, investigators suggested that a humoral factor from the spleen and BM cell suspensions might benefit the radioprotective effects [18], while later studies proved that it was attributed to the transplanted hematopoietic cells [19–21]. When Till and McCulloch discovered hematopoietic stem cells (HSCs) in the 1960s, those cells protecting animals from IR-induced lethal hematopoietic damage were HSCs [22, 23]. Remarkable progress has been subsequently made in understanding of the mechanisms by which radiation causes hematopoietic

However, the effects of space radiation on the hematopoietic system have yet to be fully understood, leading to a lack of effective countermeasure strategies thus far. In the present chapter, we mainly focus our discussion on the biological effectiveness of space radiation, such as proton and oxygen, whereby space radiation induces HSC injury, and the implication of HSC injury to IR-induced BM suppression in mouse. In addition, genomic instability, malignancies, and intestinal, brain, behavioral, and cognitive effects induced by space radiation will not be discussed

Hematopoietic stem cells often replenish the whole blood system throughout the life span of the body and maintain hematopoietic homeostasis. In Till and McCulloch's landmark work [22, 23, 26], they utilized colony-forming unit-spleen (CFU-S) assay to identify functional HSCs even while these HSCs were a mixed

here, which were extensively discussed by other investigators [24, 25].

**2. Composition of the mouse hematopoietic system**

**80**

damage.

population with different proliferating and self-renewal abilities. This pioneering research not only provided strong evidence to show in vivo HSC existence but also stimulated many investigators to define and isolate HSCs and characterize their properties in mice and humans.

In the decades since Till and McCulloch's study [22, 23, 26], multiple cell surface markers have been used to separate HSCs from other populations. For example, lineage cell surface markers, such as Ter119, CD4, CD8, B220, Gr-1, Mac-1, and NK1.1, are not detected neither in mouse multipotent progenitors (MPPs) nor in hematopoietic progenitor cells (HPCs). Both HSCs and MPPs express c-Kit and Scal-1, which are therefore named lineage negative (Lin-), c-Kit+ , and Sca-1<sup>+</sup> as LSK cells (**Figure 1**). HPCs express c-Kit, but not Sca-1, and are termed Lin<sup>−</sup>c-Kit<sup>+</sup> Sca-1<sup>−</sup>. In 2005, Kiel et al. further utilized CD150 and CD48 surface markers to distinguish HSCs and MPPs [27]. HSCs express CD150, but not CD48, and termed CD150+ CD48<sup>−</sup>LSK cells. MPPs are CD150+/−CD48+ LSK cells. Investigators also used different strategies to identify HSCs. Combination of CD34 or ThyloFlk-2<sup>−</sup> with LSK surface markers was used to isolate HSCs, named as CD34<sup>−</sup>LSK and Thy1loFlk-2<sup>−</sup>LSK cells, respectively [26]. Trumpp's group combined CD34, CD135, CD150, CD48, and LSK markers to further differentiate HSC into long-term HSCs (CD34<sup>−</sup>CD135<sup>−</sup>CD150+ CD48<sup>−</sup>LSK cells) and short-term HSCs (CD34+ CD135<sup>−</sup>CD150+ CD48<sup>−</sup>LSK cells). In addition, HSCs have a feature with highly expression of ATP-binding protein like ABCG2 and can efflux DNA-binding dye Hoechst 33342. The Hoechst-effluxing side population (SP) cells were therefore used to indicate HSC population in the case of some circumstances [28], such as 5FU and radiotherapeutic stress conditions.

It is well-documented that the hematopoietic system is organized in a hierarchical manner (**Figure 1**). The rare long-term HSCs are located at the top of the hierarchy and have the capacity to self-renew, proliferate, and differentiate into various lineages of mature blood cells though immature MPPs and HPCs [29]. The most important feature of HSCs is quiescent to maintain their self-renewal ability

#### **Figure 1.**

*Composition of mouse hematopoietic system. Long-term hematopoietic stem cell (LT-HSCs, CD34<sup>−</sup>CD135<sup>−</sup>CD150+ CD48<sup>−</sup>LSK cells) is located at the top of the hierarchy and has the ability to self-renew, proliferate, and differentiate into short-term HSCs (ST-HSC, CD34<sup>+</sup> CD135<sup>−</sup>CD150+ CD48<sup>−</sup>LSK cells) and multipotent progenitors (MPPs, CD34+ CD135+ CD150+/<sup>−</sup>CD48+ LSK cells), which can further differentiate into different progenitors, such as common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs) and their progeny megakaryocyte/erythroid progenitors (MEPs), and granulocyte/monocyte progenitors (GMPs). Progenitors can proliferate different lineages of mature blood cells.*

and potentially provide lifelong hematopoiesis. The dominant HSCs have ability to protect the whole blood system against different stress conditions [30]. Under sublethal irradiation, HSCs have been long-term damaged, which can be easily ignored in clinic because of normal cell counts from the bone marrow and peripheral blood. Damaged HSCs induced by photon-irradiation have impaired self-renewing ability, leading to bone marrow failure and death [31]. However, whether low doses of space radiation trigger long-term HSC damage remains unknown. Comparing to HSCs, MPPs and HPCs have limit or lack self-renewal ability even though they are proliferating populations. The property of MPPs and HPCs with proliferation provides a beneficial role in case of normal hematopoiesis and stress hematopoiesis. For example, in case of blood loss or infection, MPP and HPC quickly proliferate to meet the requirement of mature cell production, trying to maintain normal hematopoiesis. Under radiotherapy and chemotherapy, MPPs and HPCs can be easily depleted with acute myelosuppression because of their proliferating feature. This will lead to HSC activation, proliferation, and differentiation to reestablish MPP and HPC populations and rebuild hematopoiesis, which might result in HSC exhaustion.
