stem cells

STEM CELLS
AND
MULTIPLE SCLEROSIS
Carme Costa Riu
MS PRECEPTORSHIP 2010
STEM CELLS
Cells from whatever tissue that are characterized by the
ability to renew themselves through mitotic cell division
(self-renewing) and differentiating into a diverse range of
specialized cell types (potency).
Understanding stem cells: an overview of the science
and issues from the national academies.
The National Academies
STEM CELLS
Potency
the capacity to differentiate into specialized cell types.
http://en.wikipedia.org/wiki/stem_cell
STEM CELLS
Self-renewal
the ability to go
through
numerous
cycles of cell division
while
maintaining
the undifferentiated
state.
Stem cell
Symmetric
division
Asymmetric
division
Progenitor cell
Types of division:
- Symmetric
- Asymmetric.
Differentiated
cell
SOURCES OF PLURIPOTENT STEM CELLS
The cycle of developmental potency; M. William Lensch, Stephen Sullivan; www.abcam.com
Embryonic stem cells: derived from the inner cell mass of earlier
blastocyst or morula stage embryos. They can give rise all cell types of the
body.
The pluripotency can also be induced in somatic cells.
EMBRIONIC STEM CELLS
- Give rise all cell types.
- Relatively easy to isolate, grow and expand.
- Limitations:
*From blastocyst or nuclear transfer:
ethical concerns
*Induced pluripotency:
transduced with virus
oncogenes expression
new techniques under study
- Immunorejection:
*ESC  immunotolerance.
*Nuclear transfer or iPC  matched with the patient.
- High risk of tumours: teratomas.
SOURCES OF MULTIPOTENT STEM CELLS
- Adult, somatic or stromal stem cells.
- Derived from a developed organism.
- Multipotency: limited differentiation into
the cell types of their tissue of origin.
Regeneration and repair in multiple sclerosis: The role of cell transplantation; S. Pluchino et al.; Neuroscience Letters 456 (2009) 101–106.
MULTIPOTENT STEM CELLS
Neural Stem Cells
(NSC)
Haematopoietic Stem Cells
(HSC)
Mesenchymal Stem Cells
(MSC)
Source
CNS
Bone marrow
Bone marrow
Markers
Nestin
CD34+, CD133+,
CD45+, CD38-
CD34-, CD45-, CD14,
CD29+, CD73+, CD90+,
CD105+, CD166+
Give rise
Neurons
Astrocytes
Oligodendrocytes
Blood cells
Non-haematopoietic
stromal cells
Properties
T cells, B-cells, NK-cells,
macrophages, red blood cells,
granulocytes and other
monocytes
cells of mesodermal origin:
osteoblast, adipocytes and
chondrocytes.
Immunomodulation
Regeneration
Immunomodulation
Regeneration.
Immunomodulation
Regeneration.
Low tumour formation risk
No tumour formation
No tumour formation
Not Easy to obtain.
Easy to culture and expand
Easy to obtain, culture
and expand
Easy to obtain, culture and
expand
No autologous transplants
Autologous transplants
Autologous transplants
No ethical concerns
No ethical concerns
Genetic abnormalities trough
passages.
THERAPEUTIC PROPERTIES OF STEM CELLS
- Replacement:
migration and engraftment in the lesioned areas.
- Bystander:
in situ immunomodulation and neuroprotection.
- Immunomodulation:
inhibition dendritic cell mediated T cell proliferation.
NEURAL STEM CELLS IN EAE
Injection of adult neurospheres induces recovery in a chronic model of
multiple sclerosis
S Pluchino et al, Nature, 422 (2003) 688-694.
Methods:
EAE in C57Bl/6 mice (MOG) / Treated with TNFa, IL-1b, LPS or untreated.
Transplant of neurospheres icv and iv.
NSC migrate and pass de BBB:
NSC were found within meningeal space or around post-capillary vessels in mouse treated with
TNFa, IL-1b, LPS. In EAE mouse NSC were mainly found in the damaged areas.
Treated
Treated
EAE
EAE
NEURAL STEM CELLS IN EAE
PDGFa receptor
GFAP
30d after injection NSC were only found in
areas with demyelination and axonal loss, or
near axons undergoing active remyelination.
Nestin
NeuN
NSC differentiation: oligodendrocytes,
astrocytes, neurons or undifferentiated.
NEURAL STEM CELLS IN EAE
NSC ICV
NSC IV
- Clinical improvement.
- Glial scar reduction.
CONCLUSION:
NSC ICV
NSC IV
Control
- NSC differentiate into myelin
forming cells = REPLACEMENT
Ologodendrocytes
Astrogliosis
- Myelinating oligodendrocytes increase.
- Regulation of endogenous
oligodendroglia and reactive
astrogliosis = BYSTANDER
NSC ICV
NSC IV
Control
NEURAL STEM CELLS IN EAE
Neural Precursors Attenuate Autoimmune Encephalomyelitis by Peripheral
Immunosuppression
O Einstein et al, Ann Neurol 2007;61:209–218.
Methods:
EAE in C57Bl/6 mice (MOG). Transplant of neurospheres icv and iv.
- Clinical improvement.
-Reduced inflammation and lesions.
- NSC were found in lymph nodes
and other organs, but not in CNS.
NEURAL STEM CELLS IN EAE
NSC inhibited Bromodeoxyuridine incorporation.
NSC did not induce apoptosis.
NSC inhibited T cell activation.
NSC protected T cells.
CONCLUSION:
NSC immunoregulatory effect on T-cells = IMMUNOREGULATION
WHAT’S GOING ON IN MS AND MSC
-Already used:
Tissue repair, enzyme production in metabolic diseases,
hematopoyetic engraftment, immunosupression (GvHD and
autoimmunity).
- Limitations:
Ex vivo expansion  commom expansion protocol
 uses FCS protocols
-Good experience in EAE
Regeneration, immunomodulation, by-standard effect.
-Phase I/II studies
Preliminary safety data: safe treatment for life-threatening and
severe diseases.
Lack of control and rigor.
STEM CELLS IN MS
MS
Transplanted
Cells
Results
Bibliography
Secondary
Progressive
Autologous HSC
Progression free survival
61-73% at 2 years.
RK Burt, Blood 2003.
RA Nash, 2003.
Secondary
Progressive
Autologous HSC
Progression free survival
36-77% at 3 years.
JP Samijn, J Neurol Neurosurg Psychiatry
2006; A Fassas, Blood Rev 2003, J Neurol
2002; H Atkins, Neurol Clin 2005; MS
Freedman, Mult Scler 2007; J Xu, Chin
Med 2006; L Su, Int J Hematol 2006.
Secondary
Progressive
Autologous HSC
Progression free survival
58-75% at 3 to 6 years.
R Saccardi, Mult Scler 2006.
A Saiz, Neurologia 2008.
XS Ni, Clin Transplant 2006.
Relapsing
remitting
Autologous HSC
Progression free survival
100% at 3 years.
RK Burt, Lancet Neurol 2009.
Secondary
Progressive
Intrathecal injection
MSC
1 improvement, 7 no
differences and 2 worse
M Mohyeddin Bonab, Iran J Immunol
2007.
Relapsing
remitting
Allogenic CD34 cells
+ adipose derived
MSC
Improvement (?), only 3
cases.
NH Riordan, J Transl Med 2009.
MS and
autoimmune
diseases
Autologous HSC
Progression free survival
85% at 5 years.
D Farge, Haematologica 2009.
Clinical trial
Autologous HSC
Ongoing.
Europoean group for Blood and Marrow
Transplantation autoimmunity disease
working party database.
RR, SP, PP
Autologous HSC
Ongoing clinical trial, phase
III (2006-2012).
http://clinicaltrials.gov/ct2/show/NCT002
73364
FUTURE
International MSCT Study Group
Concensus on protocols and results valoration.
The therapeutic potential of mesenchymal stem cell
transplantation as a treatment for MS: concensus report of
the International MSCT Study Group. MS Freedman et al.
Multiple Sclerosis 16 (4) 503-510, 2010.