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 that 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 tissues - bone and blood - by providing a unique environment for stem and stromal cells to flourish while 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.

Figure 1. The regenerative cells of the bone marrow niche

a | Haematopoietic stem cells (HSCs) give rise to all mature blood cell types. A proportion of these self-renewing cells remain stem cells to maintain a pool of long-term reconstituting HSCs (LT-HSCs) and short-term reconstituting HSCs (ST-HSCs). b | Bone marrow mesenchymal stromal cells (MSCs) are multipotent, self-renewing progenitor cells that can differentiate into other cell types. CLP, common lymphoid progenitor; CMP, common myeloid progenitor; MM cell, multiple myeloma cell; MPP, multipotent progenitor; NK cell, natural killer cell.

Figure 2. The two mini-organs of the bone marrow niche

The bone marrow niche is composed of multiple cells of mesenchymal and haematopoietic lineages. A hypoxic environment, endosteal bone cells and the proximity of sinusoids and microvessel provide a unique environment for haematopoietic stem cells (HSCs) and mesenchymal stromal cells (MSCs). The union of the skeletal remodelling system and the vascular network within the bone marrow provides a unique niche that regulates whole-body homeostasis. CAR cell, CXCL12-abundant reticular cell.

Figure 3. Biochemistry of the bone marrow niche

The hypoxic environment of the niche leads to changes in substrate utilization in order to fuel cellular activity. Hypoxia induces ATM kinase, which catalyzes hypoxia inducible factor-1α (HIF-1α) activity. HIF-1α is stabilized by binding to aryl hydrocarbon receptor nuclear translocator (ARNT); the HIF-1α complex enters the nucleus and regulates a number of genes, particularly those related to glycolysis. Consequently, glucose is utilized for ATP generation through lactate production and via the pentose phosphate shunt for nucleotide synthesis that is essential for cell proliferation. Alternatively, and particularly during normoxia, HIF-1α is rapidly broken down in the proteasome via ubiquitination by proline hydroxylase domain (PHD) enzymes. AMPK, AMP kinase; GLUT1, glucose transporter 1; LDH-A, lactate dehydrogenase A; PK, protein kinase; TCA, tricarboxylic acid; VHL, von Hippel–Lindau tumor suppressor.

Figure 4. Cancer-related disruption of the bone marrow niche

The niche is an attractive milieu for certain tumour cells, owing to a number of physical, biochemical, cellular, and ionic properties. The relationship between the bone-marrow niche and infiltrating tumour cells is dynamic. a | Once tumour cells arrive in the bone marrow, they initiate a forward feedback mechanism to alter and hijack the niche, making the microenvironment even more hospitable for tumour cells. Depending on the tumour type, osteoblastic (increased bone) b | or osteolytic (decreased bone) c | lesions can occur, and feedback to accelerate tumour growth, drug resistance, and protection via dormancy of certain clones. HSC, haematopoietic stem cell; MSC, mesenchymal stromal cell.

Figure 5. HSCs and tumour cells compete for the bone marrow niche

By mimicking haematopoietic stem cells (HSCs), bone marrow-homing tumour cells often use the same signalling pathways as HSCs to colonize the niche. Eventually, tumour cells outcompete HSCs for the niche, physically displacing present cells and monopolizing the niche to block further homing of HSCs. This leads to disrupted haematopoiesis and subsequent dysregulation of the niche itself. MSC, mesenchymal stromal cell.

Figure 6. The premetastatic niche

Alterations in the bone marrow niche can affect the host response to malignancies. Premetastatic niches can be initiated in the bone marrow by distant tumour cells that send signals (e.g. within exosomes) to precondition the niche, facilitating subsequent tumour-cell infiltration and colonization of the niche. HSC, haematopoietic stem cell; MSC, mesenchymal stromal cell.

Figure 7. Niche-directed carcinogenesis

Alterations in the bone marrow niche can directly initiate malignant transformation. Niche-directed carcinogenesis is a phenomenon (demonstrated in mice) whereby the niche itself becomes abnormal, which then causes de novo tumorigenesis. Validating this phenomenon in humans will be crucial to understanding the physiological roles of the niche in tumour initiation. HSC, haematopoietic stem cell; MSC, mesenchymal stromal cell.