Mechanobiology and Primary Cilium in the Pathophysiology of Bone Marrow Myeloproliferative Diseases

Abstract

Philadelphia-Negative Myeloproliferative neoplasms (MPNs) are a diverse group of blood cancers leading to excessive production of mature blood cells. These chronic diseases, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), can significantly impact patient quality of life and are still incurable in the vast majority of the cases. This review examines the mechanobiology within a bone marrow niche, emphasizing the role of mechanical cues and the primary cilium in the pathophysiology of MPNs. It discusses the influence of extracellular matrix components, cell-cell and cell-matrix interactions, and mechanosensitive structures on hematopoietic stem cell (HSC) behavior and disease progression. Additionally, the potential implications of the primary cilium as a chemo- and mechanosensory organelle in bone marrow cells are explored, highlighting its involvement in signaling pathways crucial for hematopoietic regulation. This review proposes future research directions to better understand the dysregulated bone marrow niche in MPNs and to identify novel therapeutic targets.

Keywords: bone marrow niche; hematopoietic stem cells; mechanobiology; mesenchymal stromal cells; myeloproliferative neoplasms; primary cilium.

Figure 1

PRISMA 2020 flow diagram for new systematic reviews, which included searches of databases, registers, and other sources * [17]. This work is licensed under CC BY 4.0. To view a copy of this license, visit https://creativecommons.org/licensed/by/4.0/ (accessed on 15 June 2024).

Figure 2

Niches in the bone marrow. Adult hematopoietic stem cells (HSCs) are organized within the bone marrow microenvironment, in which two main different cellular niches are recognized: the endosteal and the perivascular niche. As depicted on the left of this Figure, the endosteal niche plays a key role in maintaining HSCs quiescence, while the perivascular niche (on the right), activates the cell cycle and promotes proliferation. Both biochemical and biomechanical factors contribute together to shape the environment. LepR, leptin recep-tor-expressing; CAR cell, cxcl12- abundant reticular cell; MSC, mesenchymal stromal cell; SCF, stem cell factor; FGF1, fibroblast growth factor 1; TGFβ, transforming growth factor β; NG2, neuron-glial 2; OSM, oncostatin M (created by Biorender.com).

Figure 3

Biomechanical signals and molecular pathways in hematopoietic stem cells (HSCs). Simplified representation of how external mechanical stimuli interact with mechanosensors like ion channels, adhesion receptor-ligand bonds, cytoskeletons, and primary cilia. Mechanosensing does impact several translational events (summarized in this Figure), although all of the molecular pathways activated are still not known. The role of the junctional interfaces is important to transmit internal forces, triggering cellular mechanical responses. See the text for a more detailed explanation (created using Biorender.com).

Figure 4

Primary cilium structure. Schematic representation of the primary cilium extending from the apical surface of cells, featuring a central core made of nine microtubule doublets (axoneme) that originate from the basal body, a modified centrosomal mother centriole. The transition zone (TZ) includes Y-shaped links that connect the axonemal microtubules to the ciliary membrane, helping to compartmentalize the organelle. Proteins and other cargos are moved anterogradely from the basal body to the tip of the axoneme by the intraflagellar transport (IFT)-B complex and kinesin motor protein, while the IFT-A complex and dynein motor protein handle retrograde transport from the tip to the basal body. The basal body is associated with the BBSome, a seven-protein complex crucial for ciliogenesis and ciliary trafficking. The ciliary membrane is enriched with specialized lipids, proteins, and receptors such as the Patched 1 (PTCH1) receptor and the Smoothened (SMO) co-receptor, which interact with various Hedgehog (HH) ligands to regulate signaling pathways (e.g., Hedgehog signaling). Refer to the text for more details. Modified using BioRender from Tiberio et al. [49].