1. Stem Cell Therapy for ARDS
顏至慶
指導教授：陳全木教授
中興大學生命科學系
中國醫藥大學附設醫院

2. Contents Introduction Stem cell Tx in other systems
Acute respiratory distress syndrome (ARDS)
Stem cells and plasticity
Stem cell Tx in other systems
Stem cell Tx for ARDS
Stem cells in lung parenchyma
Our recent report & Important reports
Mechanisms of stem cell Tx
Conclusions

3. - ARDS - Stem Cells & Plasticity
Introduction
- ARDS
- Stem Cells & Plasticity

4. Berlin Definition of ARDS
(No ALI)
(JAMA 2012; 307: )

5. Trend of Incidence of ARDS
58/ per year in USA (2005)
Declining ( )
perhaps due to:
Lung protective ventilation
Reduction of nosocomial Inf
Conservative use of blood products
(NEJM 2005; 353: ; AJRCCM 2011; 183:59-66)

6. Trend of Mortality of ARDS
Mortality: 36-44% up to 2006
Declining ( )
Perhaps due to
Lung protective ventilation
Supportive Tx: Early antibiotics, Ulcer prevention, Better fluid Tx, Nutritional & organ support
(J Clin Invest 2012; 122: ; Postgrad Med J 2011; 87:612-22)

7. Management for ARDS Early recognition and avoidance of risk factors
Initial intervention
Lung protective ventilation
Conservative fluid management
Tx for life-threatening hypoxemia => check Pplat
Pplat < 30 => Recruitment and/or High PEEP alone
Pplat > 30 => Prone position or HFV
No improvement => Inhaled NO ?
Low dose steroid after evaluation
ECMO (Crit Care Med 2010; 38: )

8. Directions of Tx. for ARDS
Treat underlying diseases
Inhibition of inflammation
Provide adequate oxygenation
Lung Protective Ventilatory Strategies
Hemodynamic support
Adequate general supportive Tx:
Infection control, Early enteral nutrition, Stress ulcer prophylaxis
Speed lung healing
Stem Cells

9. Stem Cells
Stem Cells: limitless self-renewal and differentiation, multipotent
Transit Amplifying Cells: proliferation but not self-renewal
Maturing Cells: full expression of differentiation markers, no self-renewal, no proliferation
(Fuchs E, 2000)

10. Hematopoietic & Mesenchymal Stem Cells (MSCs)
(Stem Cell Information of NIH)

11. Plasticity of Adult Stem Cells
(Yen, et al. Eur J Clin Invest 2006; 36: 310)

12. Yamanaka 山中伸彌 教授 (京都大學, 2006)
Oct3/4, Sox2, Klf4, c-Myc by retrovirus

14. Stem Cell Tx in Other Systems

15. BMCs Improved LVEF – Meta-Analysis
(Circulation 2012; 126: 551)

16. (Circulation 2012; 126: 551)

17. Stem Cells Tx for ARDS - Stem Cells in Lung Parenchyma
- Our recent report
- Important reports

18. Previous Concept of Alveolar Cells
( Circa, 1980 )

19. New Concept of Lung Stem Cells
Endogenous
SC Pool
Exogenous
SC Pool
?(Krause) ?(Kotton)
( Uhal BD, 1997 ) (Yen, et al. Eur J Clin Invest 2006; 36: 310)

20. Our Recent Report - Amniotic Fluid Stem Cells (AFSCs) from EGFP Transgenic Mice Attenuate Hyperoxia-Induced Acute Lung Injury (PLOS One 2013)

21. Myofibrobalsts
Adipocytes
Osteocytes

22. AFSCs improved survival Better than BM-MSC & embryonic fibroblast cells

23. AFSCs Attenuate Lung Injury

24. AFSCs reduced acute inflammation and apoptosis

25. AFSCs reduced inflammatory cytokines (7th days)
Immunomodulatory effects of MSCs have been proved

26. Accumulation of AFSCs within the injured lung
Greatest on day 1
Gradually decreased on the following days

27. Medium from hyperoxic lung increased AFSCs migration

28. Stem Cell Tx for ARDS (review articles)
Critical Care 2012, 16: 205
Current Opinion of Critical Care
2014, 20:

29. Key Points
Mesenchymal stem cells, bone marrow-derived mononuclear cells, endothelial progenitor cells, and embryonic or induced pluripotent stem cells => promise for ARDS.
Mechanisms:
Paracrine (antimicrobial and repair factors, KGF)
Cell–cell contact (transfer of nucleic acids and organelles => modulate immune cells)
Engraftment & differentiation
Mesenchymal stem cells: rapidly advanced to clinical testing, with two early phase clinical trials

30. Recent Reports of Stem Cell TX for ARDS

35. Intratracheal Tx with MSC Improved Survival in The LPS Model of ALI
(Chest 2010; 138: )

36. Clinical Trial of MSCs for ARDS – 12 patients

37. MSCs Tx is Safe & Feasible
(Respiratory Research 2014, 15:39)

38. Mechanisms of Stem Cell Therapy

39. Homing & Migration: Tissue- committed CXCR4 Cells Attracted by SDF-1 + Others
(Ratajczak, 2004; Feng et al., 2012)

40. Mechanisms of Stem Cell Tx
(Curr Opin Crit Care 2014,20: )

41. (Curr Opin Crit Care 2014,20:122-131)

42. Conclusions - Stem Cell Therapy
(Yen, et al. Eur J Clin Invest 2006; 36: 310)

43. 謝謝聆聽　敬請賜教