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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 Contents • Introduction – 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 Introduction - ARDS - Stem Cells & Plasticity Berlin Definition of ARDS (No ALI) (JAMA 2012; 307:2526-33) Trend of Incidence of ARDS • 58/100000 per year in USA (2005) • Declining (20012008) • perhaps due to: – Lung protective ventilation – Reduction of nosocomial Inf – Conservative use of blood products (NEJM 2005; 353: 1685-93; AJRCCM 2011; 183:59-66) Trend of Mortality of ARDS • Mortality: 36-44% up to 2006 • Declining (19972009) • Perhaps due to – Lung protective ventilation – Supportive Tx: Early antibiotics, Ulcer prevention, Better fluid Tx, Nutritional & organ support (J Clin Invest 2012; 122:2731-40; Postgrad Med J 2011; 87:612-22) 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; 38:1644-1650) Directions of Tx. for ARDS • Treat underlying diseases – Inhibition of inflammation Stem Cells • 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 Stem Cells: limitless self-renewal and differentiation, multipotent Transit Amplifying Cells: proliferation but not selfrenewal Maturing Cells: full expression of differentiation markers, no self-renewal, no proliferation (Fuchs E, 2000) Hematopoietic & Mesenchymal Stem Cells (MSCs) (Stem Cell Information of NIH) Plasticity of Adult Stem Cells (Yen, et al. Eur J Clin Invest 2006; 36: 310) Yamanaka 山中伸彌 教授 (京都大學, 2006) Oct3/4, Sox2, Klf4, c-Myc by retrovirus Stem Cell Tx in Other Systems BMCs Improved LVEF – Meta-Analysis (Circulation 2012; 126: 551) (Circulation 2012; 126: 551) Stem Cells Tx for ARDS - Stem Cells in Lung Parenchyma - Our recent report - Important reports Previous Concept of Alveolar Cells ( Circa, 1980 ) New Concept of Lung Stem Cells Endogenous SC Pool ?(Krause) ?(Kotton) ( Uhal BD, 1997 ) Exogenous SC Pool (Yen, et al. Eur J Clin Invest 2006; 36: 310) Our Recent Report - Amniotic Fluid Stem Cells (AFSCs) from EGFP Transgenic Mice Attenuate HyperoxiaInduced Acute Lung Injury (PLOS One 2013) Myofibrobalsts Adipocytes Osteocytes AFSCs improved survival Better than BM-MSC & embryonic fibroblast cells AFSCs Attenuate Lung Injury AFSCs reduced acute inflammation and apoptosis AFSCs reduced inflammatory cytokines (7th days) Immunomodulatory effects of MSCs have been proved D1 Accumulation of AFSCs within the injured lung D3 Greatest on day 1 Gradually decreased on the following days D7 Medium from hyperoxic lung increased AFSCs migration Stem Cell Tx for ARDS (review articles) Critical Care 2012, 16: 205 Current Opinion of Critical Care 2014, 20: 122-131 Key Points • Mesenchymal stem cells, bone marrowderived 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 Recent Reports of Stem Cell TX for ARDS Intratracheal Tx with MSC Improved Survival in The LPS Model of ALI (Chest 2010; 138:965-972) Clinical Trial of MSCs for ARDS – 12 patients MSCs Tx is Safe & Feasible (Respiratory Research 2014, 15:39) Mechanisms of Stem Cell Therapy Homing & Migration: Tissue- committed CXCR4 Cells Attracted by SDF-1 + Others (Ratajczak, 2004; Feng et al., 2012) Mechanisms of Stem Cell Tx (Curr Opin Crit Care 2014,20:122-131) (Curr Opin Crit Care 2014,20:122-131) Conclusions - Stem Cell Therapy (Yen, et al. Eur J Clin Invest 2006; 36: 310) 謝謝聆聽 敬請賜教