BMP-dependent, injury-induced stem cell niche as a mechanism of heterotopic ossification

Abstract

BackgroundHeterotopic ossification (HO), either acquired (aHO) or hereditary, such as fibrodysplasia ossificans progressiva (FOP), is a serious condition without effective treatment. Understanding of the core process of injury-induced HO is still severely limited.MethodsDouble-pulse thymidine analog labeling was used to explore the distinctive domains evolved in injury-induced lesions in an animal model of HO (Nse-BMP4). Histological studies were performed to see whether a similar zonal pattern is also consistently found in biopsies from patients with aHO and FOP. In vivo clonal analysis with Rainbow mice, genetic loss-of-function studies with diphtheria toxin A (DTA)-mediated depletion and lineage tracing with Zsgreen reporter mice were used to obtain further evidence that Tie2-cre-, Gli1-creERT-, and Glast-creERT-labeled cells contribute to HO as niche-dwelling progenitor/stem cells. Immunohistochemistry was used to test whether vasculature, neurites, macrophages, and mast cells are closely associated with the proposed niche and thus are possible candidate niche supportive cells. Similar methods also were employed to further understand the signaling pathways that regulate the niche and the resultant HO.ResultsWe found that distinctive domains evolved in injury-induced lesions, including, from outside-in, a mesenchymal stem cell (MSC) niche, a transient domain and an inner differentiated core in an animal model of HO (Nse-BMP4). A similar zonal structure was found in patients with aHO and FOP. In vivo clonal analysis with Rainbow mice and genetic loss-of-function studies with DTA provided evidence that Tie2-cre-, Gli1-creERT-, and Glast-creERT-labeled cells contribute to HO as niche-dwelling progenitor/stem cells; consistently, vasculature, neurites, macrophages, and mast cells are closely associated with the proposed niche and thus are possible candidate niche supportive cells. Further mechanistic study found that BMP and hedgehog (Hh) signaling co-regulate the niche and the resultant HO.ConclusionsAvailable data provide evidence of a potential core mechanism in which multiple disease-specific cellular and extracellular molecular elements form a unique local microenvironment, i.e., an injury-induced stem cell niche, which regulates the proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs). The implication for HO is that therapeutic approaches must consider several different disease specific factors as parts of a functional unit, instead of treating one factor at a time.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1107-7) contains supplementary material, which is available to authorized users.

Tendon-derived cathepsin K–expressing progenitor cells activate Hedgehog signaling to drive heterotopic ossification

“…A recent study showed that Gli1labeled adult mesenchymal stem/progenitor cells contributed to endochondral heterotopic ossification (7). Ablation of Hh signaling can inhibit the HO process in an Mkx-deficient mouse model and trauma-induced HO mouse model (35,36). Activating Hh signaling is…”

Inhibition of immune checkpoints prevents injury-induced heterotopic ossification

“…Although it is always difficult to extrapolate from animal models of disease to humans, the cellular and molecular features of human HO are very similar to what is observed in Nse-BMP4 mice. 28 Thus we hypothesize that a BMP-dependent, injury-induced stem cell niche is a common mechanism of HO 28 and that the altered immune homeostasis observed in the animal model are part of the process in humans. Importantly, we specifically used FDA-approved IC inhibitors in these studies to enhance the potential translational implications.…”

Antiosteogenic effect of arsenic trioxide, cholecalciferol, lovastatin or their combination in vitro

“…8 Recently, it was shown that local dysregulation of Hh signaling participates in the pathophysiology of murine muscle injury model of HO. 14,15 Furthermore, these lineage tracing studies suggested an involvement of Hh target transcription factor, Gli1, in endochondral bone formation. 14,15 Currently, there is no effective and safe HO prophylaxis treatment.…”

“…14,15 Furthermore, these lineage tracing studies suggested an involvement of Hh target transcription factor, Gli1, in endochondral bone formation. 14,15 Currently, there is no effective and safe HO prophylaxis treatment. Radiation therapy and indomethacin are the most widely used therapeutic approaches in the setting of post-surgical heterotopic ossification prophylaxis, with evidently many hazards and shortcomings.…”