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 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

- ARDS - Stem Cells & Plasticity 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 (2001-2008) 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 (1997-2009) 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 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 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)

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 Exogenous SC Pool ?(Krause) ?(Kotton) ( Uhal BD, 1997 ) (Yen, et al. Eur J Clin Invest 2006; 36: 310)

Our Recent Report - Amniotic Fluid Stem Cells (AFSCs) from EGFP Transgenic Mice Attenuate Hyperoxia-Induced 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

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

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 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

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