Download 骨髓幹細胞在急性肺損傷後肺修復中

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