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.

Figure 1

Schematic representation of the (a) HSC, normal stem cell and (b) LIC, leukemia-initiating cell interactions with the microenvironment. Niches provide support for self-renewal, quiescence, homing, enfrafment, and proliferation. As shown, HSCs and LSC reside in the osteoblastic or vascular niche. HSCs and LSC interact with multiple cell types (OB, OC, EC, CAR, MSC) within the BM microenvironment. Although schematically represented separately, the endosteal, and vascular niches are physically and functionally mutually involved. Candidate niche mechanisms, which regulate HSC function are also shown, including Jagged/notch, SDF1/CXCR4, SCF/c-Kit signaling. LIC quiescence, survival, and expansion are influenced by receptor kinases, adhesive receptors and signaling via matrix mediated/bound chemokines and cytokines (IL6, G-CSF, GM-CSF, KIT L, NOTCH L). LIC may secrete substance like SCF, infiltrate the niches, and take advantage of the normal hemostatic process, which enhances self-renewal and proliferation. Growth factor and other adhesion receptors signals can be targeted to overcome chemoresistance. Oxygen level, higher in the vascular niche than the osteoblastic niche under hypoxia. LIC proliferation results in expansion of hypoxic niche. HSC: hematopoietic Stem Cell, OPN: osteopontin, LIC: leukemia-initiating Cell, N-Cad: N-Cadherin, OC: osteoclast, VLA-4: very late antigen 4, OB: osteoblast, VEGFR: vascular endothelial growth factor receptor, TB: trabecular bone, SDF1: stromal growth factor 1, SCF: stem cell factor, Ang1: angiopoietin 1, HA: hyaluronic acid, ECM: extracellular matrix.