Pericyte coverage of abnormal blood vessels in myelofibrotic bone marrows

Zetterberg, Eva; Vannucchi, Alessandro M.; Migliaccio, Anna Rita; Vainchenker, William; Tulliez, M; Dickie, Renee; Hasselbalch, Hans Carl; Rogers, Rick A.; Palmblad, Jan

doi:10.3324/haematol.11013

Cited by 31 publications

(45 citation statements)

References 34 publications

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“…The control materials consisted of BM biopsies from patients with PMF (or exceptionally secondary MF) with grade II or III BM fibrosis, and from healthy controls. The patients were followed at the respective University Hospitals in Huddinge or € Orebro, Sweden, and the majority has been described previously [13,16].…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, sections were stained for CD34 and a-smooth muscle actin (SMA-a) to identify endothelial cells and pericytes, respectively. Each section was evaluated for microvessel density (MVD), expressed as the mean number of CD34 positive structures with a visible lumen and presence of intraluminal erythrocytes per 10 high power fields (HPF) using the 403 objective, and for percentage of pericyte covered vessels, as described [13]. Stainings for GATA1, CTGF, VEGF, and AGGF1 were performed with poly/monoclonal antibodies (Supporting Information Table SI).…”

Section: Methodsmentioning

confidence: 99%

“…Paraffin embedded BM biopsies were examined, and the European Consensus 0-III grading for fibrosis was applied [17]. Immunohistochemistry (IHC) and immunofluorescence (IF) stainings of microvessel markers were performed as described [13]. Briefly, sections were stained for CD34 and a-smooth muscle actin (SMA-a) to identify endothelial cells and pericytes, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…However, in a rodent correlate, the mouse model neodeltaHS, a hypomorphic Gata1 low mutation yields megakaryocytic Gata1 deficiency causing thrombocytopenia, progressive BM fibrosis and splenomegaly, mimicking the human myeloproliferative neoplasm primary myelofibrosis (PMF) [12,13]. In addition, the transient myeloproliferative disorder as well as acute megakaryocytic leukemia in Down's syndrome, both strongly associated with acquired GATA1 mutations, have BM fibrosis as a characteristic feature [8].…”

Section: Introductionmentioning

confidence: 99%

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X‐linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: Comparisons with primary myelofibrosis

et al. 2015

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X‐linked thrombocytopenia with thalassemia (XLTT) is caused by the mutation 216R > Q in exon 4 of the GATA1 gene. Male hemizygous patients display macrothrombocytopenia, splenomegaly, and a β‐thalassemia trait. We describe two XLTT families where three males were initially misdiagnosed as having primary myelofibrosis (PMF) and all five investigated males showed mild‐moderate bone marrow (BM) reticulin fibrosis. Comparative investigations were performed on blood samples and BM biopsies from males with XLTT, PMF patients and healthy controls. Like PMF, XLTT presented with high BM microvessel density, low GATA1 protein levels in megakaryocytes, and elevated blood CD34+ cell counts. But unlike PMF, the BM microvessel pericyte coverage was low in XLTT, and no collagen fibrosis was found. Further, as evaluated by immunohistochemistry, expressions of the growth factors VEGF, AGGF1, and CTGF were low in XLTT megakaryocytes and microvessels but high in PMF. Thus, although the reticulin fibrosis in XLTT might simulate PMF, opposing stromal and megakaryocyte features may facilitate differential diagnosis. Additional comparisons between these disorders may increase the understanding of mechanisms behind BM fibrosis in relation to pathological megakaryopoiesis. Am. J. Hematol. 90:E44–E48, 2015. © 2014 Wiley Periodicals, Inc.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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X‐linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: Comparisons with primary myelofibrosis

et al. 2015

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“…The pericyte vessel wall coverage is variable according to the type of vascular bed. Sixty-five percent and 71% of the adventitial sinusoid surface are covered by pericytes in the bone marrow of the rat 30 and the mouse, 31 respectively, this percentage being potentially reduced when egress of hematopoietic cells increases. In healthy humans older than 50 years, an average of 51% ( ± 20%) of the bone marrow microvessels were reported to be covered by pericytes.…”

Section: Morphological and Functional Heterogeneity Of Bone Vesselsmentioning

confidence: 99%

Assessment of bone vascularization and its role in bone remodeling

Lafage-Proust¹,

Roche²,

Langer³

et al. 2015

BoneKEy Reports

108

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Bone is a composite organ that fulfils several interconnected functions, which may conflict with each other in pathological conditions. Bone vascularization is at the interface between these functions. The roles of bone vascularization are better documented in bone development, growth and modeling than in bone remodeling. However, every bone remodeling unit is associated with a capillary in both cortical and trabecular envelopes. Here we summarize the most recent data on vessel involvement in bone remodeling, and we present the characteristics of bone vascularization. Finally, we describe the various techniques used for bone vessel imaging and quantitative assessment, including histology, immunohistochemistry, microtomography and intravital microscopy. Studying the role of vascularization in adult bone should provide benefits for the understanding and treatment of metabolic bone diseases.

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Three‐dimensional spatial mapping of the human hematopoietic microenvironment in healthy and diseased bone marrow

Bräunig

Karmhag

et al. 2023

Cytometry Pt A

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The bone marrow hematopoietic microenvironment (HME) plays a pivotal role in regulating normal and diseased hematopoiesis. However, the spatial organization of the human HME has not been thoroughly investigated yet. Therefore, we developed a three‐dimensional (3D) immunofluorescence model to analyze changes in the cellular architecture in control and diseased bone marrows (BMs). BM biopsies from patients with myeloproliferative neoplasms (MPNs) were stained sequentially for CD31, CD34, CD45, and CD271 with repetitive bleaching steps to realize five color images with DAPI as a nuclear stain. Hematopoietically normal age‐matched BM biopsies served as controls. Twelve subsequent slides per sample were stacked to create three‐dimensional bone marrow reconstructions with the imaging program Arivis Visions 4D. Iso‐surfaces for niche cells and structures were created and exported as mesh objects for spatial distribution analysis in the 3D creation suite Blender. We recapitulated the bone marrow architecture using this approach and produced comprehensive 3D models of endosteal and perivascular BM niches. MPN bone marrows displayed apparent differences compared to the controls, especially concerning CD271 staining density, megakaryocyte (MK) morphology, and distribution. Furthermore, measurements of the spatial relationships of MKs and hematopoietic stem and progenitor cells with vessels and bone structures in their corresponding niche environments revealed the most pronounced differences in the vascular nice in polycythemia vera. Taken together, using a repetitive staining and bleaching approach allowed us to establish a 5‐color analysis of human BM biopsies, which is difficult to achieve with conventional staining approaches. Based on this, we generated 3D BM models which recapitulated key pathological features and, importantly, allowed us to define the spatial relationships between different bone marrow cell types. We, therefore, believe that our method can provide new and valuable insights into bone marrow cellular interaction research.

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Pericyte coverage of abnormal blood vessels in myelofibrotic bone marrows

Cited by 31 publications

References 34 publications

X‐linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: Comparisons with primary myelofibrosis

X‐linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: Comparisons with primary myelofibrosis

Assessment of bone vascularization and its role in bone remodeling

Three‐dimensional spatial mapping of the human hematopoietic microenvironment in healthy and diseased bone marrow

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