Stem CellsKeith Channon

Department of Cardiovascular MedicineUniversity of Oxford

John Radcliffe Hospital, Oxford

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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

Stem Cells

N Engl J Med 2003;349:570-82.

Phenotypically Characterised Adult Stem Cells

Why are Stem Cells Relevant to Interventional Cardiology?

Understanding stem cell biology challenges and informs our understanding of cardiovascular disease

Stem cells may offer new therapeutic approaches in cardiovascular disease

• Multinucleate

• Negative for

Connexin 43DesmosomesCadherin

• No integration

Menasché P et al. Myoblast transplantation for heart failure. Lancet 2001

Skeletal Myoblast Cell Transplant in Ischaemic Cardiomyopathy

•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

Nature 2001;410:701-705

Red=Cardiac Myosin

a

Green=Cell Nuclei

c-kit negc-kit pos

•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

Nature Medicine 2003;9:1195-1201

Engraftment does not occur in absence of MI……..

Conclusions

• Bone marrow-derived lineage negative progenitors regenerate infarcted murine myocardium

• Autologous “skeletal lineage” progenitors improve cardiac function and survive in infarction scar

Bone Marrow Derived Stem Cells : Vascular Injury

Bone Marrow Derived Stem Cells : Atherosclerosis

Bone Marrow Derived Stem Cells :Transplant Vasculopathy

Stem Cells in Human Restenosis ?

smc-actin c-kit+

Hibbert et al. Am J Physiol 2004

Stem Cells in Human Restenosis ?

smc-actin c-kit+

Hibbert et al. Am J Physiol 2004

• Nude mice

• 1 day post femoral artery excision

• Intracardiac medium, human µvascular ECs or EPCs

Endothelial Progenitor Cells- Endothelial Progenitor Cells- Role in Endothelial MaintenanceRole in Endothelial Maintenance

high blood pressurehigh cholesterol / triglyceridessmokingdiabetesinfectionsother

RISK FACTORSRISK FACTORSCytokinesCytokinese.g. G-CSFe.g. G-CSF

STATINSSTATINSEXERCISEEXERCISE

Jonathan Hill, 2004

J. Hill et al. NEJM 2003; 348:593-600

Mean ~CK 800 U/L

TOPCARE-AMI: Late MRI follow up

TOPCARE-AMI: Late MRI follow up

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 1:1

• Primary endpoint improvement of left ventricular dysfunction at rest and during Dobutamine stress, assessed by echocardiography at 4 months.

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 n=150

• Primary endpoint improvement of left ventricular function, assessed by echocardiography and cardiac MRI at 4 months, and clinical events, up to 5 years.

Saline

GM-CSF

Saline GM-CSF

EPC Colony-Forming Capacity Following G-CSF

Day 0 Day 6 Day 14

EP

C-C

FU

0

10

20

30

40*

J. Hill et al. JACC 2005; in press

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 AE’s 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

Shirota et al. Biomaterials 2003

vWF Flk-1 LDL-Uptake

Isolation of EPCs for Stent Delivery

Stem Cells in Interventional Cardiology

vascular diseaserisk,

biology,drug therapy

cell therapy for post-MI repair

cell therapy in PCI

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