Idiopathic Pulmonary Fibrosis

Scope of the study:
Mesenchymal stem cells (MSCs) progenitor and fibroblasts generation in IPF
MSCs and the presence in IPF reticulum

1. CHEST 2016 Mesenchymal Stem Cells and Fibroblasts In Idiopathic Pulmonary Fibrosis ROBERTO CARBONE MD, FCCP ITALY

2. CHEST 2016 To study Mesenchymal stem cells (MSCs) progenitor and fibroblasts generation in IPF MSCs and the presence in IPF reticulum AIMS

3. Environmental Factors (Silica dust, Smoke Cigarette, Infectious Agents, etc) Lung Injury MSC Lung MSC Fibrocytes Type II Type I EC Endogenous Fibroblasts

4. Proliferation T cells T Regulatory Cells Epithelial Permeability Recruitment Endogenous MSC TGF β 1 KGF HGF TNF α IL-12 IgM IgG NO IL-10 PGE 2 TGF β 1 Anti-Bacterial peptides Anti-Oxidant B Cell T Cell Dendritic Cell Mechanism s of Action Adapted from S. Iyer and M Rojas. Expert Opin Biol Ther. 2008 M Rojas, N Gupta and S. Majka . 2012 Mitochondrial Transfer Microparticules TNFIP6 IL-1 β r TNF α IL-1 β IL-6 IL-8 Macrophages

5. INFLAMMATORY RESPONSE OF THE LUNG Recognition Recruitment Removal Resolution Slide courtesy of RM Strieter, MD. Fixed macrophage Antigen Capillary endothelial cell Circulating leukocyte Capillary Monocyte Infiltrating leukocyte Activated leukocyte Phagocytic leukocyte (macrophage) Chemotactic cytokine wave Fibroblast Fibrous matrix (scar issue)

6. Cellular phase Fibrotic phase Normal alveoli Cellular phase Homeostasis Fibrotic phase fibroblast ELR+ CXC ELR- CXC ELR+ CXC ELR- CXC ELR+ CXC ELR- CXC ELR+ CXC ELR- CXC Triggering event Slide courtesy of RM Strieter, MD. TNF- α IL-1 Monocyte + + – IL-1 TNF- α MØ IFN- γ IL-12 IL-18 Lymphocyte Endothelial cell Angiostasis ELR- CXC Extracellular matrix ELR+ CXC Angiogenesis Endothelial cell MOLECULAR BIOLOGY OF PULMONARY REPAIR

7. ROLE Th1 AND Th2 RESPONSES IN REPAIR PROCESS Cytokine Activation Phase Fibrotic Phase Fibroblast Slide courtesy of RM Strieter, MD. Th2 Type Th1 Type Resolution Extracellular Matrix (Fibrosis) Chemokines IL-10 (-) IL-4/IL-13 (+) IFN- γ IL-12 IL-18 (-)

8. Aging and lung diseases Meiners et al ERJ 2015 COPD Incidence (rate per 10,000 person yr) COPD COPD IPF

9. Cell  2013 153, 1194-1217DOI: (10.1016/j.cell.2013.05.039) Hallmarks of aging Lopez-Otin, Cell 2013

10. More that 800 genes are down modulated in old MSCs * B A C D Young Old

11. CHEST 2016

12. Old IPF There is an increase on senescence

13. CHEST 2016 DISCUSSION Transcriptional profiling identifies key differences that distinguish IPF from control mesenchymal progenitor cells see figure 2 Recovery and characterization of small cells from IPF and control primary mesenchymal cell lines see figure 1

14. Figure 1 The American Journal of Pathology  2014 184, 1369-1383DOI: (10.1016/j.ajpath.2014.01.012) Copyright © 2014 American Society for Investigative Pathology Terms and Conditions

15. Figure 2 The American Journal of Pathology  2014 184, 1369-1383DOI: (10.1016/j.ajpath.2014.01.012) Copyright © 2014 American Society for Investigative Pathology Terms and Conditions

16. CHEST 2016 The progeny of IPF mesenchymal progenitor cells (MPCs) display IPF fibroblast hallmarks see figure 3 DISCUSSION The progeny of a single IPF (MPCs) display the IPF fibroblast phenotype see figure 4

17. Figure 3 The American Journal of Pathology  2014 184, 1369-1383DOI: (10.1016/j.ajpath.2014.01.012) Copyright © 2014 American Society for Investigative Pathology Terms and Conditions

18. Figure 4 The American Journal of Pathology  2014 184, 1369-1383DOI: (10.1016/j.ajpath.2014.01.012) Copyright © 2014 American Society for Investigative Pathology Terms and Conditions

19. CHEST 2016 Mesenchymal progenitor cells and their progeny are present in the IPF fibrotic reticulum see figure 5 DISCUSSION

20. Figure 5 The American Journal of Pathology  2014 184, 1369-1383DOI: (10.1016/j.ajpath.2014.01.012) Copyright © 2014 American Society for Investigative Pathology Terms and Conditions

21. CHEST 2016 Genes and pathways that distinguish IPF mesenchymal progenitor cells and their progeny from their control counterparts are co-regulated Steady state mRNA profiles identify activation of cellular processes in IPF progeny consistent with their fibrotic phenotype see figure 6 DISCUSSION

22. Figure 6 The American Journal of Pathology  2014 184, 1369-1383DOI: (10.1016/j.ajpath.2014.01.012) Copyright © 2014 American Society for Investigative Pathology Terms and Conditions

23. Decrease of telomerase length Downregulation of miRNA expression, altered methylation patterns Accumulation misfolded proteins. Markers of ER stress Deficient autophagy Accumulation of dysfunctional mitochondria Senescence of MSCs Stem cell exhaustion Altered crosstalk epithelial cell-fibroblasts Hallmarks of aging in IPF-MSCs

24. The role of the stem cell in the lung niche performance Irina M. Conboy and Thomas A. Rando Cell Cycle. 2012 June 15; 11(12): 2260–2267 . “Promisingly, exogenous molecules that boost the regenerative responses of stem cells”

25. Conclusion Interventions for age-related lung diseases Cell  2013 153, 1194-1217DOI: (10.1016/j.cell.2013.05.039) Anti-inflammatory drugs Elimination of damaged cells Activation of chaperones and proteolytic systems Dietary restrictions, mTOR inhibition. AMPK and sirtuin activation Stem-cell therapies Clearance of senescence cells Telomerase reactivation

26. CHEST 2016 AKNOWLEDGMENTS Giovanni Bottino University of Genoa Italy Mauricio Rojas University of Pittsburg USA