Concise Review: Stem Cells in Osteoimmunology

Abstract

Bone remodeling is a lifelong process in which mature bone tissue is removed from the skeleton by bone resorption and is replenished by new during ossification or bone formation. The remodeling cycle requires both the differentiation and activation of two cell types with opposing functions; the osteoclast, which orchestrates bone resorption, and the osteoblast, which orchestrates bone formation. The differentiation of these cells from their respective precursors is a process which has been overshadowed by enigma, particularly because the precise osteoclast precursor has not been identified and because the identification of skeletal stem cells, which give rise to osteoblasts, is very recent. Latest advances in the area of stem cell biology have enabled us to gain a better understanding of how these differentiation processes occur in physiological and pathological conditions. In this review we postulate that modulation of stem cells during inflammatory conditions is a necessary prerequisite of bone remodeling and therefore an essential new component to the field of osteoimmunology. In this context, we highlight the role of transcription factor nuclear factor of activated T cells cytoplasmic 1 (NFATc1), because it directly links inflammation with differentiation of osteoclasts and osteoblasts. Stem Cells 2017;35:1461-1467.

Keywords: Bone; Bone marrow; Hematopoietic stem cells; Mesenchymal stem cells; Osteoblasts; Osteoclasts; Osteoimmunology; Skeletal stem cells.

Figure 1

A heterogeneous population of MSC and HSC gives rise to terminally differentiated cells with opposing functions in bone remodeling. Immunofluorescence microscopy of human bone marrow derived mesenchymal stem cells (MSC) (a–c). MSC after 14 days in culture showing homogenous expression of β-III-tubulin (green; a), and differential expression of nestin (red, b), highlighting the heterogeneous population of MSC (merged image, c). Immunofluorescence microscopy of mouse bone marrow derived HSC (d–f) cultured in the presence of MCSF and RANKL showing the homogeneous expression of α-tubulin (red, d), and the presence of multinucleated giant cells forming filamentous-actin ring structures (Phalloidin labeled actin in green, e), highlighting the heterogeneous population of osteoclast precursor cells as not all cells become terminally differentiated osteoclasts merged image (f). Original magnification for (a–c) 200x, and for (d–f) 60x.

Figure 2

Stem cell progenitors in bone homeostasis. Schematic graphical representation of the bone marrow microenvironment, one of the primary lymphoid organs, harbors immune cells including hematopoietic stem cells (HSCs), lymphocytes, monocytes/macrophages, and neutrophils, all of which interplay with bone cells such as osteoblasts, osteoclasts, and osteocytes. Schematic depicts the differentiation stages and early markers of HSC and SSC differentiation to osteoclasts and osteoblasts respectively. Long-term hematopoietic stem cells (LT-HSC) short-term hematopoietic stem cells (ST-HSC), Multipotent progenitor (MPP), Late multipotent progenitor (Late-MMP), common myeloid progenitor (CMP), monocyte (MC), macrophage (MΦ), osteoclast (OC). Skeletal stem cells (SSC), osteochondroreticular stem cell (OCR), pre-bone, stroma and cartilage progenitor (Pre-BSCP), bone, stroma and cartilage progenitor (BSCP), pre-osteoblast (pOB), osteoblast (OB) and osteocyte. Bone remodeling is regulated by macrophage colony stimulating factor (MCSF) and receptor activator for nuclear factor kappa B ligand (RANKL) at the bone surface.