Osteoblastic and Vascular Endothelial Niches, Their Control on Normal Hematopoietic Stem Cells, and Their Consequences on the Development of Leukemia

Abstract

Stem cell self-renewal is regulated by intrinsic mechanisms and extrinsic signals mediated via specialized microenvironments called “niches.” The best-characterized stem cell is the hematopoietic stem cell (HSC). Self-renewal and differentiation ability of HSC are regulated by two major elements: endosteal and vascular regulatory elements. The osteoblastic niche localized at the inner surface of the bone cavity might serve as a reservoir for long-term HSC storage in a quiescent state. Whereas the vascular niche, which consists of sinusoidal endothelial cell lining blood vessel, provides an environment for short-term HSC proliferation and differentiation. Both niches act together to maintain hematopoietic homeostasis. In this paper, we provide some principles applying to the hematopoietic niches, which will be useful in the study and understanding of other stem cell niches. We will discuss altered microenvironment signaling leading to myeloid lineage disease. And finally, we will review some data on the development of acute myeloid leukemia from a subpopulation called leukemia-initiating cells (LIC), and we will discuss on the emerging evidences supporting the influence of the microenvironment on chemotherapy resistance.

Mesenchymal stem cell aging: Mechanisms and influences on skeletal and non-skeletal tissues

“…These stromal cells can be labeled by NG2 or Prx1, whereas osteoprogenitors and osteoblasts can be labeled by osterix or osteocalcin. [19][20][21] The vascular niche is composed of vascular endothelial cells and stromal cells, with the latter being a heterogeneous population including cells positive for Nestin or Leptin receptor (Lepr) and CXCL12 (stromal cell-derived factor 1 (SDF-1)) abundant reticular (CAR) cells. Some of the cells such as Leprþ cells and NG2þ cells have been proposed to be pericytes.…”

Hematopoietic Stem Cell Niche: Role in Normal and Malignant Hematopoiesis

“…These cytokines are thought to be important as THPO and Ang-1 knockout mice have decreased numbers or defects in bone marrow HSCs. The interaction of Ang-1 with its Tie2 receptor activates β1-integrin and Ncadherin, enhances quiescence, and maintains the long term repopulating ability of HSCs; it also protects against apoptosis by activating the PI3K pathway (Lilly et al, 2011) • Osteopontin, a matrix glycoprotein expressed by the osteoblasts supports the adhesion of HSC to the osteoblastic niche and negatively regulates HSC proliferation, contributing to the maintenance of a quiescent state (Guerrouahen et al, 2011). …”

“…Both niches act together to maintain hematopoietic homeostasis or to restore it after damage (Guerrouahen et al, 2011). …”

“…At one extreme is a neoplastic growth that is dependent on dysregulated cell-cell interactions and signalling pathways within the microenvironment. At the other end of the spectrum there are malignancies that exhibit an absolute dependence on normal microenvironmental cues for disease progression, such as the expression of specific cytokines and growth factors (Guerrouahen et al, 2011).…”

Altered Calcium and Red-ox homeostasis underline defective haematopoiesis in Fanconi Anemia

“…In the osteoblastic niche the microenvironment promotes HSC maintenance and quiescence. Here BM is relatively hypoxic and HSPCs are surrounded by an habitat displaying low levels of intracellular ROS [20] . Oxygen gradient increases closer to the vascular niche and around blood vessels, where the microenvironment favours HSPC proliferation and differentiation thereby provides myeloid and lymphoid hematopoietic cells to the peripheral blood circulation [21] .…”