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Lung Development
Jamie Havrilak, PhD Postdoctoral Research Associate
Layden Lab October 28th, 2015
hDp://depts.washington.edu/envh/lung.html
Alveoli/Capillaries: Site of Gas Exchange in the Lung
Capillary
CO2
O2
Vein
Artery
Air
Alveoli/Capillaries: Site of Gas Exchange in the Lung
Capillary
CO2
O2
Vein
Artery
Air
Nkx2.1-‐ epithelium Endomucin-‐ blood vessels SMA-‐smooth muscle
hDp://depts.washington.edu/envh/lung.html
Alveolar Surface Area= 350-‐400 sq W (100-‐150 m2) Respired Air – 11,000 liters/day
Common Lung Diseases • Respiratory Distress (RDS) • Bronchopulmonary Dysplasia (BPD) • Congenital Diaphragma\c Hernia (CDH) • Asthma • Pulmonary hypertension • Lung Cancer • Emphysema • COPD
Common Lung Diseases • Respiratory Distress (RDS) • Chronic lung diseases of early infancy (BPD) • Congenital Diaphragma\c Hernia (CDH) • Asthma • Pulmonary hypertension • Lung Cancer • Emphysema • COPD • Why study lung development? • If we understand how to make a lung, we can figure out how to repair it.
Nicholas Hartsoeker 1694 Homunculus
Each of the germ layers gives rise to many different cell types
Developmental Biology, 9e, Figure 1.7
Image from Zorn and Wells, 2009
The tracheal groove, arising from the foregut endoderm, branches to give rise to the conduc\ng airways
Major Stages of the Developing Lung
I. Embryonic II. Pseudoglandular
III. Canalicular
V. Alveolar
IV. Saccular
Image modified from the Pulmonary Biology Division website hDp://www.cincinna\childrens.org/research/div/pulmonary-‐biology/faculty-‐research/whitseD-‐lab/projects.htm
Nkx2.1-‐ Lung epithelium
Lung epithelial development driven by mesenchymal signals
Rankin and Zorn, 2015, J. Cell Biochem.
FGF signaling is an essen\al component of the regulatory networks between epithelium and mesenchyme in the developing lung
• Dele\on of FGF10 results in lung agenesis, as does dele\on of its receptor FGFR2b.
Image modified from Sekine, et al.,1999
Image modified from Cardoso and KoDon, 2008
Stages of Human and Mouse Lung Development
Lungs con\nue to develop aWer birth
Havrilak and Shannon, 2015
Conception
Bud initiation
Branching morphogenesisbegins
Embryonic
Alveolar
PseudoglandularCanalicular
Saccular
Formation of alveoli
Surfactant synthesis begins
Human (weeks):
Mouse (days): E12
7w
E16
17w
E17
26w
PN4
38w
PN14
18m
E9
3w
Patterning is complete
Alveoli number increasesBirth
Conception
Bud initiation
Branching morphogenesisbegins
Embryonic
Alveolar
PseudoglandularCanalicular
Saccular
Formation of alveoli
Surfactant synthesis begins
Human (weeks):
Mouse (days): E12
7w
E16
17w
E17
26w
PN4
38w
PN14
18m
E9
3w
Patterning is complete
Alveoli number increasesBirth
Premature Birth Respiratory Distress Disrupts Lung Development
Havrilak and Shannon, 2015
Lung Morphogenesis and Differen\a\on
40 Cell Types
Need to Orchestrate Proper: Place Time Cell Types Cell Numbers Size Func\on Repair
Regula\on of Processes: Commitment Specifica\on Restric\on Differen\a\on Prolifera\on Matura\on Morphogenesis PaDerning
Interac\ons Between Mul\ple Signaling Pathways
When? Where? How much?
Rankin and Zorn, 2015, J. Cell Biochem.
Gene regulatory network governing respiratory specifica\on
hDp://www.eurostemcell.org/factsheet/lung-‐stem-‐cells-‐health-‐repair-‐and-‐disease
Genera\on and organiza\on of cell types
Why study lung stem cells and lung regenera\on?
• Currently no effec\ve treatments – Respiratory distress syndrome – Chronic obstruc\ve pulmonary disease – Idiopathic pulmonary fibrosis
• Pathways that are ac\vated during development may be ac\vated during adult lung repair
• Model human disease • New or improved clinical therapies
Induced pluripotent stem cell (iPSC)
hDps://research.cchmc.org/stemcell/iPSC
Pluripotent stem cell (PSC)-derived organoids.
Meritxell Huch, and Bon-Kyoung Koo Development 2015;142:3113-3125
© 2015. Published by The Company of Biologists Ltd
Go through many different stages before it can become a lung cell
Rankin and Zorn, 2015, J. Cell Biochem.
Interac\ons Between Mul\ple Signaling Pathways
When? Where? How much?
Rankin and Zorn, 2015, J. Cell Biochem.
Gene regulatory network governing respiratory specifica\on
Lung Morphogenesis and Differen\a\on
40 Cell Types
Need to Orchestrate Proper: Place Time Cell Types Cell Numbers Size Func\on Repair
Regula\on of Processes: Commitment Specifica\on Restric\on Differen\a\on Prolifera\on Matura\on PaDerning
How do we make a lung in a dish?
Briana R Dye et al. eLife Sciences 2015;4:e05098
Lung organoids
Briana R Dye et al. eLife Sciences 2015;4:e05098
Briana R Dye et al. eLife Sciences 2015;4:e05098
Briana R Dye et al. eLife Sciences 2015;4:e05098
In vitro differen\a\on of human PSCs (hPSCs) towards pancrea\c β-‐cells.
Rachel E. Jennings et al. Development 2015;142:3126-3137
© 2015. Published by The Company of Biologists Ltd
Lung stem cell
KoDon and Morrisey, 2014 Nature Medicine Lee, et al., 2014, Cell
Thank you!
MDB Graduate Program Amanda Middleton Pulmonary Biology Division MaB Kofron Mike MunEfering Kyle McCracken (Wells Lab) Kristen Melton (Flk-‐1mut mice)
Shannon Lab John Shannon Sui Lin Xiaofei Shangguan Jim Bridges Mike Burhans Kalpana Srivastava
Layden Lab Mike Layden Dylan FalEne-‐Gonzalez Nisha Singh Caitlin Tedeschi Courtney Turiano Suraj Pursnani Alex Mease Daniella Fodera
Ques\ons?
email [email protected]
