Stem Cells

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Stem Cells
Keith Channon
Department of Cardiovascular Medicine University
of Oxford John Radcliffe Hospital, Oxford
For more slides click here
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Adult Stem Cells

• Unique cells that are capable of self-renewal
• Have the ability to differentiate through a
  committed lineage
• Undergo further development within an adult
  organism v embryo
• They are multi(pluri)potent v totipotent

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Stem Cells
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Phenotypically Characterised Adult Stem Cells
N Engl J Med 2003349570-82.
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Why are Stem Cells Relevant to Interventional
Cardiology?
Stem cells may offer new therapeutic approaches
in cardiovascular disease
Understanding stem cell biology challenges and
informs our understanding of cardiovascular
disease
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Skeletal Myoblast Cell Transplant in Ischaemic
Cardiomyopathy

• Multinucleate
• Negative for
• Connexin 43
• Desmosomes
• Cadherin
• No integration

Menasché P et al. Myoblast transplantation for
heart failure. Lancet 2001
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Nature 2001410701-705

• Lin- c-kitPOS bone marrow cells from EGFP male
  mice to myocardium of female C57B6mouse
• Injected in peri-infarct tissue 3-5hrs after LAD
  ligation

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a
c-kit neg
c-kit pos
GreenCell Nuclei
RedCardiac Myosin
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Nature Medicine 200391195-1201

• CD117 CD90 CD34 MSCs from BM male rats
  isolated by adhesion to polystyrene, purified by
  immunoselection,
• Transfected with murine Akt by VSV retrovirus
• Permanent CAL of LAD in female rats
• 60 mins post CAL MSCs injected 5 peri-infarct
  sites

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Engraftment does not occur in absence of MI..
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Conclusions

• Bone marrow-derived lineage negative progenitors
  regenerate infarcted murine myocardium
• Autologous skeletal lineage progenitors improve
  cardiac function and survive in infarction scar

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Bone Marrow Derived Stem Cells Vascular Injury
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Bone Marrow Derived Stem Cells Atherosclerosis
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Bone Marrow Derived Stem Cells Transplant
Vasculopathy
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Stem Cells in Human Restenosis ?
c-kit
smc-actin
Hibbert et al. Am J Physiol 2004
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Stem Cells in Human Restenosis ?
c-kit
smc-actin
Hibbert et al. Am J Physiol 2004
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• Nude mice
• 1 day post femoral artery excision
• Intracardiac medium, human µvascular ECs or EPCs

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Endothelial Progenitor Cells- Role in
Endothelial Maintenance
Jonathan Hill, 2004
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J. Hill et al. NEJM 2003 348593-600
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Mean CK 800 U/L
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TOPCARE-AMI Late MRI follow up
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TOPCARE-AMI Late MRI follow up
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The STIMULATE Trial

• Title Multicenter, randomized controlled study of
  transplantation of bone marrow-derived progenitor
  cells into infarct vessels of patients following
  an acute myocardial infarction, acutely
  re-vascularised by percutaneous intervention.
• Principal Investigators Prof. Dr. A. M. Zeiher
  J.W. Goethe, University of Frankfurt
• Sponsor Cardio-Cell, Zutphen, the Netherlands
  (parent Cryo Cell using subsid MainGen in
  Frankfurt )
• Monitoring CorTrial, Berlin
• Objective To assess the safety and efficacy of
  intracoronary therapy with bone marrow-derived
  autologous progenitor cells with respect to
  improvement of myocardial function after an acute
  myocardial infarction treated by PTCA.
• Design Multi-center,Randomized 11
• Primary endpoint improvement of left ventricular
  dysfunction at rest and during Dobutamine stress,
  assessed by echocardiography at 4 months.

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THE PRIMATIVE Trial Leicester

• Percutaneous Randomised Infusion of Marrow
  Aspirate To Improve Ventricular Efficiency
• Principal Investigators Tony Gershlick, Nilesh
  Samani et al.
• Objective Assess the safety and efficacy of
  intracoronary therapy with bone marrow-derived
  autologous progenitor cells delivered at salvage
  PCI (DES) after acute MI, either early or late.
• Design Single-center, Randomized,
  Placebo-Controlled n150
• Primary endpoint improvement of left ventricular
  function, assessed by echocardiography and
  cardiac MRI at 4 months, and clinical events, up
  to 5 years.

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Saline
GM-CSF
Saline
GM-CSF
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EPC Colony-Forming Capacity Following G-CSF
J. Hill et al. JACC 2005 in press
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G-CSF and In-stent Restenosis after MIKang et
al. Lancet 2004

• Patients undergoing PCI with stenting of culprit
  artery following MI (3 days to 9 months)
  randomized to G-CSF apheresis / IC infusion,
  control
• No AEs associated with G-CSF treatment
• At 6 month F/U, improved treadmill time, LVEF,
  SPECT perfusion in cell infusion group
• In-stent restenosis determined in 7/10 G-CSF
  treated patients, 0/1 control
• Study terminated

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Isolation of EPCs for Stent Delivery
vWF
Flk-1
LDL-Uptake
Shirota et al. Biomaterials 2003
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Stem Cells in Interventional Cardiology
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Future Directions

• Circulating or Bone Marrow Progenitor Cells?
• Harvest or not, which subset?
• Statins
• Cytokine stimulation to release- e.g. CXCR4, new
  drugs
• Circulating / Bone Marrow progenitor cells
  clinical trials- need to be blinded, placebo
  controlled, with hard end points
• Understanding mechanisms remains critical to
  evaluating and targeting real benefits