Title: Chemical%20and%20Physical%20Regulation%20of%20Stem%20Cells%20and%20Progenitor%20Cells:%20Potential%20for%20Cardiovascular%20Tissue%20Engineering%20(Review)%20%20Ngan%20F.%20Huang,%20Randall%20J.%20Lee,%20Song%20Li
1Chemical and Physical Regulation of Stem Cells
and Progenitor Cells Potential for
Cardiovascular Tissue Engineering (Review)Ngan
F. Huang, Randall J. Lee, Song Li
- By Deepika Chitturi
- BIOE 506
- Spring 2009
2Why Cardiovascular Tissue Engineering?
- Leading Cause of Mortality (every 34 sec)
- Expensive (250 billion)
- Myocardial Infarction (MI aka heart-attacks)
- Coronary Artery Occlusion
- Cardiomyocyte Cell Death
- Non-generation
- Formation of Scar Tissue
- Dilation of Chamber Cavities
- Aneurysmal Thinning of Walls
- REDUCED PUMPING CAPACITY
- Driving Force Shortage of Donors
3Potential Stem Progenitor Cells
- MSCs Mesenchymal Stem Cells
- HSCs Hematopoietic Stem Cells
- EPCs Endothelial Precursor Cells
- ESCs Embryonic Stem Cells
- Skeletal Myoblasts
- Resident Cardiac Stem Cells
4Perfect Tissue Engineered Construct
- CELL SOURCE
- SOLUBLE CHEMICAL FACTORS
- EXTRACELLULAR MATRIX (ECM)
5Cardiovascular Tissue Engineering (I)
- Cell Source
- Embryonic Stem Cells
- Adult Stem Cells
- Soluble Chemical Factors
- VEGF (ESCs, HSCs, EPCs)
- TGF-ß (ESCs, MSCs, HSCs, EPCs)
- BMP (ESCs)
- 5-azacytidine (MSCs)
- FGF (ESCs, HSCs, EPCs)
- IGF (HSCs, EPCs)
6Cardiovascular Tissue Engineering (II)
- Extracellular Matrix
- Natural Polymers
- Matrigel In vivo injection for MI, ESC
differentiation - Collagen In vivo injection for MI, Vascular
grafts - Hyalinuric Acid Vascular grafts
- Alginate ESC differentiation
- Fibrin In vivo injection for MI, Vascular
conduits - Decellularized Vessel Vascular conduits
- Synthetic Polymers
- Poly-L-lactic Acid (PLLA) ESC differentiation
- Poly-lactic-co-glycolic acid (PLGA) ESC
differentiation - Polyglycotic Acid (PGA) Vascular grafts
- Peptide Nanofibers In vivo injection for MI
- Poly-diol-citrates and Poly-glycerol-sebacate
General tissue engineering
7Extracellular Matrix
- Dr. Vasif Harsirci- Middle East Technical
University (Biomedical Unit)
Effects of Cordyceps militaris extract on
angiogenesis and tumor growth1 Hwa-seung YOO,
Jang-woo SHIN2, Jung-hyo CHO, Chang-gue SON,
Yeon-weol LEE, Sang-yong PARK3, Chong-kwan CHO4
Department of East-West Cancer Center, College
of Oriental Medicine, Daejeon University, Daejeon
301-724
8Role of Matrix Materials for Structural Support
- hESCs cultured in porous PLGA/PLLA scaffolds
coated with Matrigel or Fibronectin vs. Matrigel
alone or fibronectin-coated dishes (Levenberg et
al) - 3-D polymer structure promoted differentiation
(neural tissue, cartilage, liver and blood
vessels) - Formation of 3-D blood vessels
- Fibronectin-coated dishes
- Failure to organize into 3-D structure
- Matrigel
- Organization into 3-D structure
- No cell differentiation
- Conclusion
- Large inter-connected pores cell colonization
- Pores smaller than 100 nm limit diffusion of
nutrients and gases - 3-D great surface area, higher expression of
integrins
9Role of Matrix Topography and Rigidity
- Topography Cell Organization, alignment and
differentiation - Nano-scale and micro-scale matrix topography
affects organization and differentiation of stem
cells - hMSCs undergo skeletal reorganization and orient
themselves in the direction of microgrooves and
nano-fibers (Patel et al) - Stiffness/Rigidity Cells tend to migrate toward
more-rigid surfaces and cells on soft matrix have
a low rate of DNA synthesis and growth (Engler et
al) - Assembly of focal adhesions and contractile
cytoskeleton structure depend on rigidity
10Cardiovascular Tissue Engineering Models
- In vitro differentiation method engineering
constructs with structural and functional
properties as native tissues before
transplantation - In situ method relies on host environment to
remodel the chemical and physical environment for
cell growth and function - Ex vivo approach excision of native tissues and
remodeling them in culture
11Cardiovascular Tissue Engineering Proposed Models
- Injectable Stem Cells and Progenitor Cells for in
situ cardiac tissue engineering - Vascular Conduits
12Injectable Stem Cells and Progenitor Cells for in
situ cardiac tissue engineering
- Delivery modes for myocardial constructs
- Cardiac patching
- Cell Injection
- Cell-polymer injection
- Less invasive than solid scaffolds
- Adopt shape and form of host environment
- Delivery vehicles (with cells and GFs)
- Polymers Collagen I, Matrigel, Fibrin, Alginate
and Peptide Nanofibers
13Injectable delivery of Polymers
- Collagen I, Matrigel and Fibrin
- Higher capillary density than saline control
treatment - Migration of vascular cells into infarcted region
for neovascularization - Fibrin MSCs (Huang et al)
- Promotes angiogenesis
- ESCs Matrigel (Kofidis et al)
- Greater improvements in contractility after 2
weeks - Rat bone marrow mononuclear cells (MNCs) Fibrin
(Ryu et al) - Enhanced neovascularization
- Development of larger vessels
- Extensive tissue regeneration
- Graft survival 8 weeks
14Treatment using Stem and Progenitor Cells alone
- TGF-ß-treated CD117 rat MNCs (Li et al)
- Differentiation into myogenic lineage
- Enhanced vascular density
- Retrovirally transduced Akt1-overexpressing MSCs
(Mangi et al, Laflamme et al) - Reduced intramyocardial inflammation
- 80 of lost myocardial volume regeneration
- Normal systolic and diastolic functions
restoration - Cardiac enriched hESCs in athymic rats (Laflamme
et al) - Cardiomyocyte growth
- No teratomas
- 7-fold increase in graft size in 4 weeks
- Potential regeneration of human myocardium in rat
heart
15Vascular Conduits
- Goal To create functional conduit as a bypass
graft (small, non-thrombogenic, native mechanical
properties) - Limitations to vein grafts
- Availability
- 35 10-year failure
- Synthetic Vascular Grafts
- Poly-ethylene-terephthalate
- Expanded poly-tetrafluoroethylene
- Polyurethane
- Limitation
- Inside diameter larger than 5 mm
- Frequent thrombosis and occlusions in smaller
grafts
16Vascular ConduitsProposed Models
- ECs SMCs in a tubular PGA porous scaffold
(Niklason et al) - In vivo implantation patent for 2 weeks
development of histological features consistent
with vascular structures - EPC-seeded grafts (Kaushal et al)
- Remained patent for more than 130 days
- Acellular control grafts occluded in 15 days
- Vessel-like characteristics contractility and
nitric-oxide mediated vascular relaxation - EPCs derived from umbilical cord blood using 3D
porous polyurethane tubular scaffolds in a
biomimetic flow system (Schmidt et al) - In 12 days, EPCs lined lumen of VGs and formed
endothelial morphology
17Vascular ConduitsProposed Models
- MSC seeded nanofibrous vascular grafts (Hashi et
al) - Patent for at least 8 weeks
- Synthesis and organization of collagen and
elastin - EC monolayer formed on lumen surfaces
- SMCs were recruited and formed
18Conclusion
- Understanding the effect of chemical and physical
cues for regulation of stem-cell survival,
differentiation, organization and morphogenesis
into tissue-like structures most important!! - Cardiovascular repair, Cardiac therapies after MI
and engineering of vascular conduits