Lung Physiology. Jamie Havrilak, PhD Postdoctoral Research Associate Layden Lab October 26th, 2018

Transcription

1 Lung Physiology Jamie Havrilak, PhD Postdoctoral Research Associate Layden Lab October 26th, 2018

2 Nkx2.1- Lung epithelium Endomucin- Vasculature

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5 Alveoli/Capillaries: Site of Gas Exchange in the Lung

6 Alveoli/Capillaries: Site of Gas Exchange in the Lung Artery CO 2 Air O 2 Capillary Vein

7 Alveoli/Capillaries: Site of Gas Exchange in the Lung Artery CO 2 Air O 2 Capillary Nkx2.1- epithelium Endomucin- blood vessels SMA-smooth muscle Vein

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9 Alveolar Surface Area= sq ft ( m 2 ) Respired Air 11,000 liters/day

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11 proximal Generation and organization of cell types distal

12 Epithelium -Ciliated cells -Goblet cells -Club cells -Alveolar type 1 and type 2 cells proximal distal Mesenchyme -Endothelial cells -Smooth muscle cells -fibroblasts -Pericytes

13 Distal Alveolus

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17 Lung Diseases Respiratory Distress (RDS) Bronchopulmonary Dysplasia (BPD) Congenital Diaphragmatic Hernia (CDH) Asthma Pulmonary hypertension Lung Cancer Emphysema COPD Cystic fibrosis

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19 Cystic Fibrosis

20 Common Lung Diseases Respiratory Distress (RDS) Chronic lung diseases of early infancy (BPD) Congenital Diaphragmatic Hernia (CDH) Asthma Pulmonary hypertension Lung Cancer Emphysema COPD Cystic fibrosis Why study lung development? If we understand how the lung develops, we can figure out how to repair it.

21 Stages of Human and Mouse Lung Development Alveolar Saccular Canalicular Pseudoglandular Embryonic Mouse (days): E9 E12 E16 E17 PN4 PN14 Human (weeks): 3w 7w 17w 26w 38w 18m Conception Branching morphogenesis begins Surfactant synthesis begins Birth Alveoli number increases Bud initiation Patterning is complete Formation of alveoli Lungs continue to develop after birth Havrilak and Shannon, 2015

22 Alveolar Saccular Canalicular Pseudoglandular Embryonic Mouse (days): E9 E12 E16 E17 PN4 PN14 Human (weeks): 3w 7w 17w 26w 38w 18m Conception Branching morphogenesis begins Surfactant synthesis begins Birth Alveoli number increases Bud initiation Patterning is complete Formation of alveoli Havrilak and Shannon, 2015 Premature Birth Respiratory Distress Disrupts Lung Development

23 Each of the germ layers gives rise to many different cell types Developmental Biology, 9e, Figure 1.7

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25 Image from Zorn and Wells, 2009

26 The tracheal groove, arising from the foregut endoderm, branches to give rise to the conducting airways

27 Nkx2.1- Lung epithelium Early Stages of Lung Development I. Embryonic I. Embryonic E-cadherinendoderm Endomucin- Vasculature I. Embryonic II. Pseudoglandular II. Pseudoglandular II. Pseudoglandular Mesenchyme Havrilak and Shannon, Lung Development 2015 Image modified from the Pulmonary Biology Division website Epithelium

28 Lung Branching Morphogenesis Metzger et al, Nature 2008

29 Later Stages of Lung Development in the Mouse III. Canalicular IV. Saccular V. Alveolar V. Alveolar V. Alveolar

30 Lung Branching Morphogenesis Metzger et al, Nature 2008

31 Tissue interactions govern early lung morphogenesis Importance of Lung Mesenchyme Lung mesenchyme is essential for lung development Branching and differentiation of the epithelium depends on a close association with the lung mesenchyme. Mesenchyme Epithelium

32 Lung mesenchyme is necessary for lung epithelial branching Wessells, 1970

33 Lung Mesenchyme (M) Attracts Lung Epithelium (E) E M Mesenchymal inducers are diffusible

34 Lung epithelial development driven by mesenchymal signals How do we induce lung formation? Rankin and Zorn, 2015, J. Cell Biochem.

35 FGF signaling is an essential component of the regulatory networks between epithelium and mesenchyme in the developing lung Fgf10- is expressed in distal lung mesenchyme Signals to Fgf receptors in epithelium Deletion of FGF10 results in lung agenesis, as does deletion of its receptor FGFR2b. Image modified from Sekine, et al.,1999 Image modified from Cardoso and Kotton, 2008 Image modified from Min, et al.,1998 Genes and Dev

36 Interactions Between Multiple Signaling Pathways When? Where? How much? Gene regulatory network governing respiratory specification Rankin and Zorn, 2015, J. Cell Biochem.

37 Lung Morphogenesis and Differentiation 50 Cell Types Need to Orchestrate Proper: Regulation of Processes: Place Time Cell Types Cell Numbers Size Function Repair Commitment Specification Restriction Differentiation Proliferation Maturation Morphogenesis Patterning

38 Translational applications Currently no effective treatments Respiratory distress syndrome Chronic obstructive pulmonary disease Idiopathic pulmonary fibrosis Pathways that are activated during development may be activated during adult lung repair Model human disease (lung organoids) New or improved clinical therapies

39 Pluripotent stem cell (PSC)-derived organoids. Meritxell Huch, and Bon-Kyoung Koo Development 2015;142: Published by The Company of Biologists Ltd

40 Induced pluripotent stem cell (ipsc)

41 Meritxell Huch, and Bon-Kyoung Koo Development 2015;142:

42 Go through many different stages before it can become a lung cell Rankin and Zorn, 2015, J. Cell Biochem.

43 Interactions Between Multiple Signaling Pathways Gene regulatory network governing respiratory specification Rankin and Zorn, 2015, J. Cell Biochem.

44 How do we make a lung in a dish? Briana R Dye et al. elife Sciences 2015;4:e05098

45 Briana R Dye et al. elife Sciences 2015;4:e05098 Lung spheroids

46 Briana R Dye et al. elife Sciences 2015;4:e05098

47 3D Lung Organoids Chen, et al., 2017, Nature Cell Biology

48 Potential application of lung organoids in modeling human diseases Chen, et al., 2017, Nature Cell Biology

49 Thank you! Questions?