78
as the spatial arrangement of vasculature and the distribution of many different cell
types populating the BM. Therefore, in the absence of supporting evidence from
in vivo quantitative measurements, model predictions must be used to assess the
effects of different parameters on the O 2 tension distribution in the BM. The model
described by Kumar et al. considered three possible vessel arrangements to simulate
oxygen level variations under various conditions [132]. They suggested that hypoxic,
and even anoxic, regions could be found in the BM, assuming that the cells’ oxygen
consumption is constant and that the density of arterioles in the BM is low.
On the other hand, qualitative observations in the study by Parmar et al. demonstrated that HSCs are distributed according to oxygen availability in the BM [175].
Staining with pimonidazole and sectioning revealed the oxygen gradient throughout
the BM, showing that HSCs more likely reside at the lower end of the gradient.
These results are in agreement with other in vitro studies suggesting that hypoxia
supports the maintenance of stemness [45, 64, 69]. Moreover, BM transplantation
studies have shown that BM-derived EPCs enhance neovascularization and the formation of arteries [231, 235]. The renewal of EPCs in the BM depends on the differentiation dynamics of HSCs, which are regulated by the microenvironments (i.e.,
the niches) they reside in. Osteoblasts, bone cell progenitors, bind to each other and
to HSCs via adhesion molecules to form the osteoblastic niche that is located far
from the sinusoidal arteries. Researchers have discovered the existence of another
type of niche within the BM, the vascular niche, which is located closer to the sinusoidal arteries than the osteoblastic niche. The differences in physicochemical factors within the various niches play fundamental roles in controlling the dynamics of
HSC migration and differentiation. Since the vascular niche’s close proximity to
arteries means that it is richer in O 2 than the osteoblastic niche, Heissnig’s group
hypothesized that HSCs are in a quiescent state in the osteoblastic niche’s severe
hypoxic conditions [92]. When vasculogenesis is necessary in neighboring tissues,
specific cell signaling stimulates the migration of HSCs from the osteoblastic niche
to the more oxygenated vascular niche, where HSCs can switch from their quiescent
state to a proliferative state. The proliferation and differentiation of HSCs reconstitute the EPC pool in the vascular niche before they enter the circulation.
Wound healing, another situation where tissue hypoxia is prevalent, consists of a
series of events that includes new vasculature formation, which is regulated by varying O 2 levels. Platelets interfere with microcirculation in the wounded tissue, followed by the release of coagulation factors to reinforce the clotting process.
Histamine and bradykinin, secreted by mast cells, also influence the microcirculation
by enhancing vascular permeability and arteriolar vasodilation, thereby increasing
the blood flow rate [11, 102]. Recruitment of leukocytes and macrophages into the
damaged tissue is followed by their activation in response to several growth factors
(GFs) and integrins. High rates of O 2 consumption in activated macrophages, along
with perturbation of the microcirculation, lead to a further decrease in O 2 levels and
result in hypoxia [204], which leads to the accumulation of HIF1α at the wound site
[246]. Albina et al. [9] showed that the HIF1α mRNA of inflammatory cells peaks
about 6 h after injury. On the other hand, HIF1α protein levels could be detected
between 1 and 5 days after wounding. More recently, Zhang et al. [246] demonM. R. Blatchley et al.
as the spatial arrangement of vasculature and the distribution of many different cell
types populating the BM. Therefore, in the absence of supporting evidence from
in vivo quantitative measurements, model predictions must be used to assess the
effects of different parameters on the O 2 tension distribution in the BM. The model
described by Kumar et al. considered three possible vessel arrangements to simulate
oxygen level variations under various conditions [132]. They suggested that hypoxic,
and even anoxic, regions could be found in the BM, assuming that the cells’ oxygen
consumption is constant and that the density of arterioles in the BM is low.
On the other hand, qualitative observations in the study by Parmar et al. demonstrated that HSCs are distributed according to oxygen availability in the BM [175].
Staining with pimonidazole and sectioning revealed the oxygen gradient throughout
the BM, showing that HSCs more likely reside at the lower end of the gradient.
These results are in agreement with other in vitro studies suggesting that hypoxia
supports the maintenance of stemness [45, 64, 69]. Moreover, BM transplantation
studies have shown that BM-derived EPCs enhance neovascularization and the formation of arteries [231, 235]. The renewal of EPCs in the BM depends on the differentiation dynamics of HSCs, which are regulated by the microenvironments (i.e.,
the niches) they reside in. Osteoblasts, bone cell progenitors, bind to each other and
to HSCs via adhesion molecules to form the osteoblastic niche that is located far
from the sinusoidal arteries. Researchers have discovered the existence of another
type of niche within the BM, the vascular niche, which is located closer to the sinusoidal arteries than the osteoblastic niche. The differences in physicochemical factors within the various niches play fundamental roles in controlling the dynamics of
HSC migration and differentiation. Since the vascular niche’s close proximity to
arteries means that it is richer in O 2 than the osteoblastic niche, Heissnig’s group
hypothesized that HSCs are in a quiescent state in the osteoblastic niche’s severe
hypoxic conditions [92]. When vasculogenesis is necessary in neighboring tissues,
specific cell signaling stimulates the migration of HSCs from the osteoblastic niche
to the more oxygenated vascular niche, where HSCs can switch from their quiescent
state to a proliferative state. The proliferation and differentiation of HSCs reconstitute the EPC pool in the vascular niche before they enter the circulation.
Wound healing, another situation where tissue hypoxia is prevalent, consists of a
series of events that includes new vasculature formation, which is regulated by varying O 2 levels. Platelets interfere with microcirculation in the wounded tissue, followed by the release of coagulation factors to reinforce the clotting process.
Histamine and bradykinin, secreted by mast cells, also influence the microcirculation
by enhancing vascular permeability and arteriolar vasodilation, thereby increasing
the blood flow rate [11, 102]. Recruitment of leukocytes and macrophages into the
damaged tissue is followed by their activation in response to several growth factors
(GFs) and integrins. High rates of O 2 consumption in activated macrophages, along
with perturbation of the microcirculation, lead to a further decrease in O 2 levels and
result in hypoxia [204], which leads to the accumulation of HIF1α at the wound site
[246]. Albina et al. [9] showed that the HIF1α mRNA of inflammatory cells peaks
about 6 h after injury. On the other hand, HIF1α protein levels could be detected
between 1 and 5 days after wounding. More recently, Zhang et al. [246] demonM. R. Blatchley et al.