3D pulmospheres serve as a personalized and predictive multicellular model for assessment of antifibrotic drugs
Ranu Surolia, Fu Jun Li, Zheng Wang, Huashi Li, Gang Liu, Yong Zhou, Tracy Luckhardt, Sejong Bae, Rui-ming Liu, Sunad Rangarajan, Joao de Andrade, Victor J. Thannickal, Veena B. Antony
Ranu Surolia, Fu Jun Li, Zheng Wang, Huashi Li, Gang Liu, Yong Zhou, Tracy Luckhardt, Sejong Bae, Rui-ming Liu, Sunad Rangarajan, Joao de Andrade, Victor J. Thannickal, Veena B. Antony
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Resource and Technical Advance Pulmonology Therapeutics

3D pulmospheres serve as a personalized and predictive multicellular model for assessment of antifibrotic drugs

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal progressive fibrotic lung disease characterized by the presence of invasive myofibroblasts in the lung. Currently, there are only two FDA-approved drugs (pirfenidone and nintedanib) for the treatment of IPF. There are no defined criteria to guide specific drug therapy. New methodologies are needed not only to predict personalized drug therapy, but also to screen novel molecules that are on the horizon for treatment of IPF. We have developed a model system that exploits the invasive phenotype of IPF lung tissue. This ex vivo 3D model uses lung tissue from patients to develop pulmospheres. Pulmospheres are 3D spheroids composed of cells derived exclusively from primary lung biopsies and inclusive of lung cell types reflective of those in situ, in the patient. We tested the pulmospheres of 20 subjects with IPF and 9 control subjects to evaluate the responsiveness of individual patients to antifibrotic drugs. Clinical parameters and outcomes were also followed in the same patients. Our results suggest that pulmospheres simulate the microenvironment in the lung and serve as a personalized and predictive model for assessing responsiveness to antifibrotic drugs in patients with IPF.

Authors

Ranu Surolia, Fu Jun Li, Zheng Wang, Huashi Li, Gang Liu, Yong Zhou, Tracy Luckhardt, Sejong Bae, Rui-ming Liu, Sunad Rangarajan, Joao de Andrade, Victor J. Thannickal, Veena B. Antony

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Figure 6

Correlation between pulmosphere invasiveness and disease progression in patients with IPF.

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Correlation between pulmosphere invasiveness and disease progression in ...
(A) Relationship between clinical outcomes in individual patients and invasiveness of patient pulmosphere. These 8 patients with IPF were not on any medication directed to IPF. Progressors were defined as those patients with a drop in forced vital capacity (FVC) >10% or a drop in DLCO >15% in 12 months or death. (B) Relationship between patient disease progression and pulmosphere invasiveness in response to nintedanib and pirfenidone. Five patients were on nintedanib, and four patients were on pirfenidone (red represents progressors and black represents nonprogressors. Median values of ZOI >1 represent pulmospheres nonresponsive to the treatment, and median values of ZOI <1 represent pulmospheres responsive to drug treatment. (C) Number of patients whose pulmospheres were responsive to nintedanib only (green), pirfenidone only (blue), either nintedanib or pirfenidone (gray), or neither (red). (D) Individual patient responses to nintedanib and pirfenidone. Patient 19 responded to both nintedanib and pirfenidone, with greater inhibition of invasiveness of pulmospheres with nintedanib than pirfenidone. Patient 13 responded only to nintedanib. Patient 6 responded only to pirfenidone. Patient 14 did not respond to nintedanib or pirfenidone. All P values, compared with untreated pulmospheres, 2-tailed paired t test. Data were obtained from 5 pulmosphere for each group (untreated, nintedanib treated, and pirfenidone treated) per patient. “Response” is defined as a decrease in the ZOI% of each patient’s pulmosphere after treatment with nintedanib or pirfenidone as compared with untreated control.