Progress in clinical applications
of PSCs in 2018
Trounson A. et al. Nature Reviews Molecular Cell Biology 17, 194–200 (2016) doi:10.1038/nrm.2016.10
Martin Pešl
TZKM – Dep. of Biology and 1st IKAK LFMU
The bench to bedside pathway
Knoepfler PS Adv Drug Deliv Rev. 2015 Mar;82-83:192-6.
• 213040 Clinical Intervenentional studies (total)
• 12126 studies: heart, cardiac, coronary
• 3520 studies : heart failure
• 237 studies: heart stem cell
• 1 study: heart human embryonic (ESCORT)
transplantation of cardiac progenitor, feasibility/safety
• 2 studies: heart human induced pluripotent
- SOLELY in vitro phenotyping
Why?
• human heart has limited potential for
regeneration (0,01%/y in healthy adult)
• the loss of cardiomyocytes during course
of cardio-myopathy and ischaemic injury
can result in heart failure and death
What to do?
• current status
– prevention – non smoking, education, lifestyle, lipids…
– AC Inhibitor – lowering blood pressure, reverse remodeling
– Betablocker – reducing adrenergic stimulation = lower
oxygen need and consumption
– Diuretics – reduces volume overload
– etc… symptomatic treatment
– Bypass / Angioplasty / Transplantation… in time?
• cardiac repair is strategy to regenerate functionally
viable myocardium after insult as myocardial infarction to
prevent or heal heart failure…
How?
• cells/ tissues / vessels
• growth factors / cytokines
• origin:
endogenouse repair– original tissue
autologouse – other organs
allogenic – other human(s)
xenogenic – other species
• number of different strategies…
Bosniak Z. 3rd Dubrovni Cardiology Highlihts lecture
Source
?
––
Sanganalmath S Bolli R Circ Res. 2013 Aug 30; 113(6): 810–834
Skeletal Myoblasts?
• precursors of satellite cells (SKMs)
• muscle biopsies, proliferative + resistant to
ischaemia and hypoxia
• no functional coupling of SKMs with the
myocardium in vivo = fail to contract
synchronously with the native myocardium
• the MAGIC trial - no significant
improvement in LV function = discontinued
Bone Marrow-Derived Stem Cells
(BMCs) unselected ?
• in circulation
– contribute to myocytes renewal
– (cell fusion and transdifferentiation)
• harvested from pelvic bones of patients
• TOPCARE-AMI and BALANCE trial
- intracoronary BMCs 10-11% increase LVEF (5Y)
• meta- analysis: over 3000 patients have been treated with BMCs
– overall LVEF (+3.96%)
– smaller infarct size (∼−4.03%)
– clinical significance?
– limited data on mortality, recurrence of MI, and rehospitalization for heart failure
– no of carcinogenesis, arrhythmias, or any other adverse effects
• haematopoietic stem cells (HSCs)
• mesenchymal stem cells (MSCs)
• endothelial progenitor cells (EPCs)
• optimal the mixture of stem-like cells
Bone Marrow-Derived Stem Cells
clinical trial in Brno
Mesenchymal Stem Cells
(MSCs) selected?
• Bone Marrow - LVEF was increased by approximately
6.7% at 6 months, an inverse dose response, 20 million
better than 200 million cells, - the POSEIDON-pilot
• Umbilical cord matrix in 18-month follow-up, global LVEF
improved by 5% no arrhythmias or immuno side effects
• Adipose-Derived Mesenchymal Stem Cells.
harvested and expanded
o MHC class II antigens,
differentiate in to cardiomyocytes and endothelial cells
upon induction
the PRECISE study cells stabilized the scar size in
patients with advanced ischaemic heart disease (not
reduction of scar size or increase LVEF)
Cardiac Stem Cells
(CSCs )?
• resident stem-like cells, self-renewing cells able to differentiate into
a 3 cell lineages
• low proportion (0.01%) of native cardiomyocytes = low turnover rate
• meta-analysis 1970 animals improvement in LVEF by approximately
12%
• SCIPIO study phase I, c-kit+ CSCs - ischaemic MI, CSCs from right
atrial appendage CABG
– 1 million of cells administered to 16 patients intracoronary 4 months after CABG
increase in LVEF 12.3% at 12 months injection / no tumour formation
– 4–8% of transplanted CSCs colonized / persisted in the myocardium 1y
– effect of paracrine factors released by injected cells modulating the
proliferation of the host cardiac cells?
Cardiosphere-Derived Cells
(CSps)?
• in vitro cultured myocardial biopsies form spheroids
• self-renewal, positive for progenitor cell markers (c-kit,
CD-34, Sca-1, and Nkx2.5)
• heterogeneous mixture of cardiac stem cells,
differentiating progenitors and differentiated
cardiomyocytes
• enhance cardiac function, angiogenic formation, and
paracrine factor secretion (supporting cells)
• the CADUCEUS - decreased scar size of 12.3% at 12
months - no improvement in global LVEF
• large size may embolize capillary
• lack MHC II antigen = allogeneic CDCs trials
Embryonic Stem Cells
(ESCs)?
• derived from the inner cell mass of the early embryo in the
blastocyst stage
• self-renewing, clonogenic, and capable of differentiating into
any type of cell in the adult
• atrial-like, ventricular-like, sinus nodal-like, Purkinje-like cells
• beat spontaneously and synchronously
• teratomas after transplantation because of the unlimited
differentiation potential of ESCs - need for selection
• ethical concerns, potential genetic instability, risk of immune
rejection - the ESCORT study
induced Pluripotent Stem Cells
(iPSCs)
• forced expression of OCT4, SOX2, KLF4, and c-MYC
transcription factors reprogram terminally differentiated
• cells - resemble embryonic stem cells
• iPSCs can be derived from individual patients for
autologous transplantation
• risk of teratoma formation, the low efficiency of
cardiogenic differentiation, high costs, and timeconsuming
methods
• diagnostic methods – phenotype analyses and on
demand patient specific drugs testing
Direct reprogramming?
• additional slide according to question :-)
• M. Ieda, J.-D. Fu, P. Delgado-Olguin et al.,
“Direct reprogramming of fibroblasts into
functional cardiomyocytes by defined
factors,” Cell, vol. 142, no. 3, pp. 375–386,
2010.
Medicine paradigm shift!
Gillray J. Bloodletting 1804, World History Archive