Navigating the bone marrow niche: translational insights and cancer-driven dysfunction

Abstract

The bone marrow niche consists of stem and progenitor cells destined to become mature cells such as haematopoietic elements, osteoblasts or adipocytes. Marrow cells, influenced by endocrine, paracrine and autocrine factors, ultimately function as a unit to regulate bone remodelling and haematopoiesis. Current evidence highlights the bone marrow niche is not merely an anatomic compartment; rather, it integrates the physiology of two distinct organ systems, the skeleton and the marrow. The niche has a hypoxic microenvironment that maintains quiescent haematopoietic stem cells (HSCs) and supports glycolytic metabolism. In response to biochemical cues and under the influence of neural, hormonal, and biochemical factors, marrow stromal elements, such as mesenchymal stromal cells (MSCs), differentiate into mature, functioning cells. However, disruption of the niche can affect cellular differentiation, resulting in disorders ranging from osteoporosis to malignancy. In this Review, we propose that the niche reflects the vitality of two distinct tissues—bone and blood—by providing a unique environment for stem and stromal cells to flourish whilst simultaneously preventing disproportionate proliferation, malignant transformation or loss of the multipotent progenitors required for healing, functional immunity and growth throughout an organism’s lifetime. Through a fuller understanding of the complexity of the niche in physiologic and pathologic states, the successful development of more-effective therapeutic approaches to target the niche and its cellular components for the treatment of rheumatic, endocrine, neoplastic and metabolic diseases becomes achievable.

Adipose, Bone, and Myeloma: Contributions from the Microenvironment

“…These three main cell types together make up what is known as the “BMU”—the basic multicellular unit—that is responsible for maintaining skeletal mass and integrity and healing bones after fracture. These cells also form the endosteal niche which is often referred to in the context of hematopoietic stem cell (HSC) renewal [3]. These endosteal niche components are key players in skeletal response to diseases such as myeloma.…”

“…Marrow adipocytes have long been ignored as they are often viewed as inert “filler cells” rather than the metabolically active and communicative cells they are [3, 9]. Recent work has demonstrated a more complex role for bone marrow adipose tissue (MAT) within the BM niche [10] than previously acknowledged.…”

Hallmarks of Bone Metastasis

“…The dynamic nature of bone is the consequence of its constant remodeling of old or damaged bone by osteoclasts of the hematopoietic macrophage/monocyte lineage, followed by the formation of new mineralized bone matrix by osteoblasts of the mesenchymal lineage. Moreover, bone is an endocrine organ, whose cells are capable of regulating (and being regulated by) the central nervous system, energy and glucose metabolism, and gonadal function [2]. …”

Downregulation of Blood Monocyte HLA-DR in ICU Patients Is Also Present in Bone Marrow Cells

“…When such BM analysis was normal (n = 9) (conclusion made by a blinded hematologist), the results were used to determine “normal” ranges of HLA-DR expression in BM monocyte. Finally, the normal values for blood parameters were determined using blood samples from 28 healthy volunteers (10 males, 34 [18] y/o).…”

“…This micro-environment increases myelopoiesis and decreases lymphopoiesis [15–17]. Although hematopoiesis has been investigated in hematological diseases and cancer in humans [18], it has not been described in intensive care patients with acute inflammation. In a burnt mice model [19, 20] it has been demonstrated a hypo-reactivity of developing monocytes and DC in the BM and their subsequent migration to the periphery.…”