Neurogenic Heterotopic Ossifications Recapitulate Hematopoietic Stem Cell Niche Development Within an Adult Osteogenic Muscle Environment

Abstract

Hematopoiesis and bone interact in various developmental and pathological processes. Neurogenic heterotopic ossifications (NHO) are the formation of ectopic hematopoietic bones in peri-articular muscles that develop following severe lesions of the central nervous system such as traumatic cerebral or spinal injuries or strokes. This review will focus on the hematopoietic facet of NHO. The characterization of NHO demonstrates the presence of hematopoietic marrow in which quiescent hematopoietic stem cells (HSC) are maintained by a functional stromal microenvironment, thus documenting that NHOs are neo-formed ectopic HSC niches. Similarly to adult bone marrow, the NHO permissive environment supports HSC maintenance, proliferation and differentiation through bidirectional signaling with mesenchymal stromal cells and endothelial cells, involving cell adhesion molecules, membrane-bound growth factors, hormones, and secreted matrix proteins. The participation of the nervous system, macrophages and inflammatory cytokines including oncostatin M and transforming growth factor (TGF)-β in this process, reveals how neural circuitry fine-tunes the inflammatory response to generate hematopoietic bones in injured muscles. The localization of NHOs in the peri-articular muscle environment also suggests a role of muscle mesenchymal cells and bone metabolism in development of hematopoiesis in adults. Little is known about the establishment of bone marrow niches and the regulation of HSC cycling during fetal development. Similarities between NHO and development of fetal bones make NHOs an interesting model to study the establishment of bone marrow hematopoiesis during development. Conversely, identification of stage-specific factors that specify HSC developmental state during fetal bone development will give more mechanistic insights into NHO.

Keywords: ectopic hematopoietic niche; inflammation; macrophages; muscle environment; neurogenic heterotopic ossifications.

FIGURE 1

Macroscopic and microscopic views of NHO. (A) 3D scan of a NHO (white arrow) located in the right hip of a patient; (B) NHO biopsy resected during surgery displaying vascularized medullary cavities (scale bar 1 cm); (C) Alcian Blue-Nuclear Red staining of an NHO section showing the endochondral ossification process with the presence of chondrocytes (ch) and osteocytes (oc) (scale bar 100 μm). Hematoxylin-Phloxine-Safran staining of an NHO section showing the presence of (D) osteoblasts (ob), osteocytes (oc), and medullar cavities displaying adipocytes (ad), hematopoietic cells (he) (scale bar 100 μm) and (E) a megakaryocyte (black arrow) (scale bar 50 μm).

FIGURE 2

Schematic representation of mechanisms involved in ectopic hematopoietic bone development in NHO pathology. NHOs are the results of an endochondral ossification within peri-articular muscles of TBI/SCI adult patients. NHOs are characterized by the formation of a trabecular bone tissue housing HSC niches. A wide range of regulatory mechanisms are suggested to be involved in NHO pathogenesis including altered neuronal control, inflammation, macrophages and profound changes in muscle tissue environment. The singular localization of NHOs suggests a role of muscle-resident mesenchymal cells such as PDGFRα⁺ FAPs and bone metabolism in the development of ectopic hematopoiesis in adults. CNS, central nervous system; ECM, extra-cellular matrix; ECs, endothelial cells; FAP, fibro-adipogenic progenitor; HPA, hypothalamic-pituitary-adrenal; HSC, Hematopoietic stem cells; MSC, mesenchymal stromal cells; NHO, neurogenic heterotopic ossification; PR, peripheral response; SCI, spinal cord injury; SNS, sympathetic nervous system; TBI, traumatic brain injury.