Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction

Gaskill, Christa; Carrier, Erica J.; Kropski, Jonathan A.; Bloodworth, Nathaniel C.; Menon, Swapna; Foronjy, Robert; Taketo, Makoto Mark; Hong, Charles C.; Austin, Eric D.; West, James; Means, Anna L.; Loyd, James E.; Merryman, W. David; Hemnes, Anna R.; Langhe, Stijn De; Blackwell, Timothy S.; Klemm, Dwight J.; Majka, Susan M.

doi:10.1172/jci88629

Cited by 37 publications

(78 citation statements)

References 102 publications

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“… 52 , 53 , 74 , 192 , 193 Our recent studies validated the ATP binding cassette G2 (ABCG2) as a reasonable label for perivascular adult mesenchymal progenitors, with the caveat that low dose tamoxifen is required for specificity. 194 …”

Section: Adult Lung Mesenchymal Progenitors Angiogenesis and Tissuementioning

confidence: 99%

“…Because ABCG2 is present at the cell surface, we have been able to isolate populations of adult lung MPC from lung tissue explants from normal and disease lungs and characterize them in parallel to the murine models and cells. 36 , 55 , 194 , 195 We have been able to define tissue-specific signatures of MPC as well as pathways related to signaling, matrix, inflammation, and angiogenesis disrupted in disease. 194 – 196 …”

Section: Adult Lung Mesenchymal Progenitors Angiogenesis and Tissuementioning

confidence: 99%

“…The validation of ABCG2 as a marker of adult mesenchymal progenitors enabled us to determine their relationship to pericytes as well as putative function using an inducible murine lineage tracing model system. 36 , 166 , 194 The selection of ABCG2 as a marker to define this lung mesenchymal progenitor population was based on historical evidence that the expression of this multi-drug resistance transporter selects for a “side population” of cells that demonstrate stem cell-like properties in adult tissues. 191 , 197 – 203 Side population selection was used to identify multipotent mesenchymal and vascular precursors in the lung.…”

Section: Abcg2 Mesenchymal Progenitor Cells and Angiogenesismentioning

confidence: 99%

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Deregulated angiogenesis in chronic lung diseases: a possible role for lung mesenchymal progenitor cells (2017 Grover Conference Series)

et al. 2017

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Chronic lung disease (CLD), including pulmonary fibrosis (PF) and chronic obstructive pulmonary disease (COPD), is the fourth leading cause of mortality worldwide. Both are debilitating pathologies that impede overall tissue function. A common co-morbidity in CLD is vasculopathy, characterized by deregulated angiogenesis, remodeling, and loss of microvessels. This substantially worsens prognosis and limits survival, with most current therapeutic strategies being largely palliative. The relevance of angiogenesis, both capillary and lymph, to the pathophysiology of CLD has not been resolved as conflicting evidence depicts angiogenesis as both reparative or pathologic. Therefore, we must begin to understand and model the underlying pathobiology of pulmonary vascular deregulation, alone and in response to injury induced disease, to define cell interactions necessary to maintain normal function and promote repair. Capillary and lymphangiogenesis are deregulated in both PF and COPD, although the mechanisms by which they co-regulate and underlie early pathogenesis of disease are unknown. The cell-specific mechanisms that regulate lung vascular homeostasis, repair, and remodeling represent a significant gap in knowledge, which presents an opportunity to develop targeted therapies. We have shown that that ABCG2pos multipotent adult mesenchymal stem or progenitor cells (MPC) influence the function of the capillary microvasculature as well as lymphangiogenesis. A balance of both is required for normal tissue homeostasis and repair. Our current models suggest that when lymph and capillary angiogenesis are out of balance, the non-equivalence appears to support the progression of disease and tissue remodeling. The angiogenic regulatory mechanisms underlying CLD likely impact other interstitial lung diseases, tuberous sclerosis, and lymphangioleiomyomatosis.

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Section: Adult Lung Mesenchymal Progenitors Angiogenesis and Tissuementioning

confidence: 99%

Section: Adult Lung Mesenchymal Progenitors Angiogenesis and Tissuementioning

confidence: 99%

Section: Abcg2 Mesenchymal Progenitor Cells and Angiogenesismentioning

confidence: 99%

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Deregulated angiogenesis in chronic lung diseases: a possible role for lung mesenchymal progenitor cells (2017 Grover Conference Series)

et al. 2017

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“…In addition, reduced expression of bone morphogenic protein receptor 2 (BMPR2) and reduced BMP signalling promote EnMT, suggesting that the balance between TGF-β and BMP signalling determines the phenotype of primitive ECs 13 . Primitive ECs are found in the vasculature of different adult organ systems, and these primitive ECs may be the source of highly proliferative endothelial progenitors and clonally expandable stem-like ECs, but also mesenchymal progenitor cells in the adult pulmonary vasculature [14][15][16][17] . Clonal expansion further contributes to neovascularization after ischemia in the systemic circulation 18 .…”

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confidence: 99%

Clonally selected primitive endothelial cells promote occlusive pulmonary arteriopathy and severe pulmonary hypertension in rats exposed to chronic hypoxia

Bhagwani

Farkas

Harmon

et al. 2020

Sci Rep

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one current concept suggests that unchecked proliferation of clonally selected precursors of endothelial cells (ecs) contribute to severe pulmonary arterial hypertension (pAH). We hypothesized that clonally selected ECs expressing the progenitor marker CD117 promote severe occlusive pulmonary hypertension (PH). The remodelled pulmonary arteries of PAH patients harboured CD117 + ecs. Rat lung CD117 + ecs underwent four generations of clonal expansion to enrich hyperproliferative ecs. The resulting clonally enriched ECs behaved like ECs, as measured by in vitro and in vivo angiogenesis assays. The same primitive ECs showed a limited ability for mesenchymal lineage differentiation. Endothelial differentiation and function were enhanced by blocking TGF-β signalling, promoting bone morphogenic protein (BMP) signalling. The transplantation of the EC clones caused arterio-occlusive PH in rats exposed to chronic hypoxia. these ec clones engrafted in the pulmonary arteries. Yet cessation of chronic hypoxia promoted lung cell apoptosis and resolution of vascular lesions. In conclusion, this is to the best of our knowledge, the first report that clonally enriched primitive ECs promote occlusive pulmonary arteriopathy and severe pH. these primitive ec clones further give rise to cells of endothelial and mesenchymal lineage as directed by BMP and TGF-β signaling. Pulmonary arterial hypertension (PAH) remains a devastating disease with dismal prognosis. The pulmonary arteries of PAH patients have lesions of varying severity including formation of neointima, which obstructs the normal blood flow, and complex multicellular plexiform lesions. A current concept suggests that dysregulated programmed cell death, or apoptosis of ECs causes unchecked proliferation of a subset of apoptosis-resistant ECs 1,2. The ECs retain a hyperproliferative and apoptosis-resistant phenotype even in culture 3. These abnormal ECs in the plexiform lesions of PAH patients may originate from primitive endothelial-like stem cells by clonal selection 4. This concept of primitive cells as source of aberrant ECs in PAH is supported by the findings of markers of primitive stem-like cells in the lung vascular lesions 5-7. Likewise, hyperproliferative pulmonary artery smooth muscle cells may also be derived from progenitor cells in PAH 8,9. During vascular development, primitive ECs

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“…Microcirculation and its effects are a focus of present and future research that aim to improve diagnostic and treatment strategies. Moreover, it has recently been demonstrated that treatment at an early stage of microvascular dysfunction may be most effective for delaying or reversing the disease processes, thus improving the outcome and survival of patients at risk for pulmonary vascular disease [ 32 ]. The authors also suggested that this knowledge may be applied toward microvascular dysfunction observed in the skin [ 32 ].…”

Section: Main Textmentioning

confidence: 99%

Evaluation of microvascular endothelial function in patients with infective endocarditis using laser speckle contrast imaging and skin video-capillaroscopy: research proposal of a case control prospective study

2017

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ObjectiveInfective endocarditis is a severe condition with high in-hospital and 5-year mortality. There is increasing incidence of infective endocarditis, which may be related to healthcare and changes in prophylaxis recommendations regarding oral procedures. Few studies have evaluated the microcirculation in patients with infective endocarditis, and so far, none have utilized laser-based technology or evaluated functional capillary density. The aim of the study is to evaluate the changes in the systemic microvascular bed of patients with both acute and subacute endocarditis. This is a cohort study that will include adult patients with confirmed active infective endocarditis according to the modified Duke criteria who were admitted to our center for treatment. A control group of sex- and age-matched healthy volunteers will be included. Functional capillary density, which is defined as the number of spontaneously perfused capillaries per square millimeter of skin, will be assessed by video-microscopy with an epi-illuminated fiber optic microscope. Capillary recruitment will be evaluated using post-occlusive reactive hyperemia. Microvascular flow will be evaluated in the forearm using a laser speckle contrast imaging system for the noninvasive and continuous measurement of cutaneous microvascular perfusion changes. Laser speckle contrast imaging will be used in combination with skin iontophoresis of acetylcholine, an endothelium-dependent vasodilator, or sodium nitroprusside (endothelium independent) to test microvascular reactivity.ResultsThe present study will contribute to the investigation of microcirculatory changes in infective endocarditis and possibly lead to an earlier diagnosis of the condition and/or determination of its severity and complications. Trial registration ClinicalTrials.gov ID: NCT02940340.

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Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction

Cited by 37 publications

References 102 publications

Deregulated angiogenesis in chronic lung diseases: a possible role for lung mesenchymal progenitor cells (2017 Grover Conference Series)

Deregulated angiogenesis in chronic lung diseases: a possible role for lung mesenchymal progenitor cells (2017 Grover Conference Series)

Clonally selected primitive endothelial cells promote occlusive pulmonary arteriopathy and severe pulmonary hypertension in rats exposed to chronic hypoxia

Evaluation of microvascular endothelial function in patients with infective endocarditis using laser speckle contrast imaging and skin video-capillaroscopy: research proposal of a case control prospective study

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