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Chemical 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. Why Cardiovascular Tissue Engineering?. Leading Cause of Mortality (every 34 sec)

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by deepika chitturi bioe 506 spring 2009

Chemical 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

why cardiovascular tissue engineering
Why 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
        • Driving Force: Shortage of Donors
potential stem progenitor cells
Potential 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
perfect tissue engineered construct
Perfect Tissue Engineered Construct
cardiovascular tissue engineering i
Cardiovascular Tissue Engineering (I)
  • Cell Source
      • Embryonic Stem Cells
      • Adult Stem Cells
  • Soluble Chemical Factors
      • VEGF (ESCs, HSCs, EPCs)
      • TGF-β(ESCs, MSCs, HSCs, EPCs)
      • BMP (ESCs)
      • 5-azacytidine (MSCs)
      • FGF (ESCs, HSCs, EPCs)
      • IGF (HSCs, EPCs)
cardiovascular tissue engineering ii
Cardiovascular 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
extracellular matrix
Extracellular Matrix

Matrigel Angiogenesis

PLLA Angiogenesis

Dr. Vasif Harsirci- Middle East Technical University (Biomedical Unit)

Effects of Cordycepsmilitaris extract on angiogenesis and tumor growth1Hwa-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;

role of matrix materials for structural support
Role 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
role of matrix topography and rigidity
Role 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
cardiovascular tissue engineering models
Cardiovascular 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
cardiovascular tissue engineering proposed models
Cardiovascular Tissue Engineering Proposed Models
  • Injectable Stem Cells and Progenitor Cells for in situ cardiac tissue engineering
  • Vascular Conduits
injectable stem cells and progenitor cells for in situ cardiac tissue engineering
Injectable 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
injectable delivery of polymers
Injectable 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
treatment using stem and progenitor cells alone
Treatment using Stem and Progenitor Cells alone
  • TGF-β-treated CD117+ rat MNCs (Li et al)
    • Differentiation into myogenic lineage
    • Enhanced vascular density
  • Retrovirallytransduced 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
vascular conduits
Vascular 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
vascular conduits proposed models
Vascular Conduits—Proposed 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
vascular conduits proposed models17
Vascular Conduits—Proposed 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
  • 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