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Pivotal Role of Capillary Endothelial Cells on Lung Regeneration in Murine Emphysema Model
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A4198 - Pivotal Role of Capillary Endothelial Cells on Lung Regeneration in Murine Emphysema Model
Author Block: S. Hisata1, S. M. Cloonan2, B. Palikuqi3, B. Kunar3, B. Ding3, S. Rafii3, A. M. Choi2; 1Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Shimotuke-shi, Japan, 2Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, United States, 3Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, United States.
RATIONALE: Endothelial dysfunction has been implicated in mediating the pathogenesis of emphysema in patients with chronic obstructive pulmonary disease (COPD). Pulmonary capillary endothelial cells (PCECs) play a pivotal role in sustaining the homeostasis of lung function in response to stress, extending beyond their traditional role of facilitating oxygen delivery. A dysfunctional endothelial cell niche may therefore disrupt alveolar structure and subsequent tissue repair in emphysema. In this study, we sought to determine whether intravascular transplantation of PCECs could stimulate lung regeneration in a murine emphysema model.
METHODS: PCECs were isolated from C57/BL6 murine lungs and were transfected with the adenovirus E4ORF1 gene, which allows PCECs to survive and grow outside the body. Experimental emphysema was induced via the intratracheal instillation of elastase in 8-week-old C57/BL6 mice. Five hundred thousand PCECs were injected retro-orbitally 7 and 14 days following elastase instillation. Pulmonary function was evaluated at Day28, and mean cord lengths were calculated on formalin-fixed lung sections. Engrafted PCECs and proliferating cells were evaluated with fluorescence activated cell sorting and immunohistochemical analysis.
RESULTS: We first investigated the physiological and biological function of endothelial cells in a murine emphysema model. Following elastase injection, the proportion of lung endothelial cells to total lung cells was significantly decreased. Phosphorylated VEGFR2 and VEGF levels in the lung were significantly decreased from 7 days, up to 56 days after elastase treatment. We next investigated the therapeutic effects of PCEC transplantation. Despite minimal engraftment, PCEC treatment significantly decreased airspace enlargement, evaluated with mean cord length and pulmonary function test. Furthermore, recipient capillary endothelial cells proliferated and lung cell death decreased after PCEC treatment. The proportion of endothelial cells to total cells in the lung was restored via PCEC treatment. In contrast, neither adipose tissue-derived endothelial-cells nor lung fibroblasts recapitulated the effects of PCECs.
CONCLUSIONS: Capillary endothelial cells are dysregulated in murine emphysema lung. PCEC treatment ameliorates emphysema in a tissue-specific and cell-type-specific manner.
Supported by National Institutes of Health grants P01 HL108801, R01 HL079904, R01 HL055330 and R01 HL060234 (A.M.K.C.), K99 HL125899 (S.M.C), R01 HL130826 (B.D), and R01 HL119872 (S.R)
Author Block: S. Hisata1, S. M. Cloonan2, B. Palikuqi3, B. Kunar3, B. Ding3, S. Rafii3, A. M. Choi2; 1Division of Pulmonary Medicine, Department of Medicine, Jichi Medical University, Shimotuke-shi, Japan, 2Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, United States, 3Ansary Stem Cell Institute, Division of Regenerative Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, United States.
RATIONALE: Endothelial dysfunction has been implicated in mediating the pathogenesis of emphysema in patients with chronic obstructive pulmonary disease (COPD). Pulmonary capillary endothelial cells (PCECs) play a pivotal role in sustaining the homeostasis of lung function in response to stress, extending beyond their traditional role of facilitating oxygen delivery. A dysfunctional endothelial cell niche may therefore disrupt alveolar structure and subsequent tissue repair in emphysema. In this study, we sought to determine whether intravascular transplantation of PCECs could stimulate lung regeneration in a murine emphysema model.
METHODS: PCECs were isolated from C57/BL6 murine lungs and were transfected with the adenovirus E4ORF1 gene, which allows PCECs to survive and grow outside the body. Experimental emphysema was induced via the intratracheal instillation of elastase in 8-week-old C57/BL6 mice. Five hundred thousand PCECs were injected retro-orbitally 7 and 14 days following elastase instillation. Pulmonary function was evaluated at Day28, and mean cord lengths were calculated on formalin-fixed lung sections. Engrafted PCECs and proliferating cells were evaluated with fluorescence activated cell sorting and immunohistochemical analysis.
RESULTS: We first investigated the physiological and biological function of endothelial cells in a murine emphysema model. Following elastase injection, the proportion of lung endothelial cells to total lung cells was significantly decreased. Phosphorylated VEGFR2 and VEGF levels in the lung were significantly decreased from 7 days, up to 56 days after elastase treatment. We next investigated the therapeutic effects of PCEC transplantation. Despite minimal engraftment, PCEC treatment significantly decreased airspace enlargement, evaluated with mean cord length and pulmonary function test. Furthermore, recipient capillary endothelial cells proliferated and lung cell death decreased after PCEC treatment. The proportion of endothelial cells to total cells in the lung was restored via PCEC treatment. In contrast, neither adipose tissue-derived endothelial-cells nor lung fibroblasts recapitulated the effects of PCECs.
CONCLUSIONS: Capillary endothelial cells are dysregulated in murine emphysema lung. PCEC treatment ameliorates emphysema in a tissue-specific and cell-type-specific manner.
Supported by National Institutes of Health grants P01 HL108801, R01 HL079904, R01 HL055330 and R01 HL060234 (A.M.K.C.), K99 HL125899 (S.M.C), R01 HL130826 (B.D), and R01 HL119872 (S.R)
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