LE DONNE NELLE STEM:LE MALATTIE NEURODEGENERATIVE
100esperte.it, una delle scienziate si racconta
Maria Pia Abbracchio, Università Statale di Milano
Presidente Fondazione Filarete per le Bioscienze e l’innovazione
Milano - 15 Marzo 2017
Milano- 15 marzo 2017
Le due grandi emergenzesanitarie del mondo
occidentale:l’invecchiamento e le malattie
neurodegenerative
University of Texas
Medical School at Houston
University College London, London, UK Università degli Studi di Milano
Milano- 15 marzo 2017
Aging, neurodegenerative diseases and
the coming epidemic
Aging: the numbersGlobally, the 65-plus demographic isestimated to triple from 524 millionin 2010 to about 1.5 billion by 2050Aging associated-neurodegenerative diseases:
• Stroke• Cerebral trauma• Parkinson’s disease• Huntinghton’s disease• Alzheimer’s disease• Multiple Sclerosis• Amiotrophic lateral sclerosis
From: Jesus Avila, R&D on Ageing: the Biomedical Viewpoint
Milano- 15 marzo 2017
Cognitive defects is a common hallmarkof neurodegenerative diseases!
Not Just a Movement Disorder: Cognitive Changes in PDBy Laura Marsh, M.D.
Distractibility, disorganization, forgetfulness, and difficulties with planning: it frequently comes asa surprise to people with Parkinson’s disease (PD) and their families that “cognitive changes”— alterations in memory, attention, and thinking — are often part of PD. After all, in 1817, whenJames Parkinson first described the “shaking palsy” he said that, “the senses and intellect wereuninjured.” While he was correct in most of his assertions, Dr. Parkinson did miss the mark withthis claim.
Milano- 15 marzo 2017
The promise of stem cells for neuro-rejenerative therapies
Embryonic cells transplantation for cell substitution therapyin Parkinson’s, Alzheimer’s, multiple sclerosis, ALS, stroke…
Milano- 15 marzo 2017
Stem cell transplantationin Parkinson’s disease
• Many patients have experiencedtransplant rejection or dyskinesias
• Transplanted cells can differentiate to cells other than dopaminergic neurons
• In some cases, cells can generate tumors• Transplanted cells can get sick !!
However….
Some patients have shown clear beneficial effects (disease amelioration, needfor lower doses of medications, long term survival of transplanted cells)
Important proof-of-concept that cell substitution therapycould work!
Milano- 15 marzo 2017
One of the biggest discoveries
of the last 20 years:
There still are stem-like cells in the adult brain!!
…but also throughout the entire brain’s parenchyma !!
- “Activated” reactive astrocytic precursors
- Oligodendrocyte precursor cells (OPCs)
…and these adult stem cells arepresent not only in neurogenic areas….
Hippocampus, an area
involved in learning and memory
Milano- 15 marzo 2017
In the adult brain, OPCs continuously proliferate and differentiate to generate new myelinating cells
…that can restore damaged myelin around neuronal
processes and re-establish cell-to-cell communication
in disease
GPR17-negative GPR17+GPR17+
NG2-NG2+
OLIGODENDROCYTE
PRECURSOR CELLPRE-IMMATURE
OLIGODENDROCYTE
MATURE
OLIGODENDROCYTE
Our contribution to the field:
GPR17-negative
GPR17, a receptor involved inthe differentiation and maturation of adult stem cells
Milano- 15 marzo 2017
BMBP/NF
CMBP/NF
CTRL GALINEX
negative GPR17+GPR17+
NG2-NG2+
OLIGODENDROCYTE
PRECURSOR CELL
PRE-IMMATURE
OLIGODENDROCYTE
NEURONMYELINATING
OLIGODENDROCYTE
MATURE
OLIGODENDROCYTE
GPR17-negative
OPCs are highly plastic cells and under some conditions….
they can also generate new neurons!!
et al, Purinergic Signalling, 2016Milano- 15 marzo 2017
Milano- 15 marzo 2017
GPR17, a new target for myelinating therapies
From Fumagalli M, Lecca D, Abbracchio MP, Neuropharmacology, 2015
shared patent between UniMI to develop
new regenerative strategies multiple sclerosis via GPR17Pia Abbracchio e
Ivano Eberini GPR17ALS – Marta Fumagalli
Milano- 15 marzo 2017
Bru
ker
Ava
nce
II4
.7T
Vev
o2
10
0 V
isu
alS
on
ics
Gelosa P et al., submitted 2016
Milano- 15 marzo 2017
Marschallinger J et al., Nature Communications, 2015
Treatment of old mice with montelukast, a drug acting via GPR17, rejuvenates their brains and restores learning and memory to the level of young mice
Milano- 15 marzo 2017
Antagonization
Instruction
Olig2-VP16 overexpression
antagonises endogenous Olig2 function
Pax6
overexpression
Doublecortin-expressing
newborn neurons (12-19%)
in vivo
transduction
DCX
GFP
Buffo et al., PNAS 102, 18183-18188 2005
DCX: doublecortin
GFP: green fluorescent
protein
proliferating reactive progenitor cell
Olig2VP16GFP virusPax6GFP virus
Adult neural stem cell
Molecular biology approachCell instruction by gene engineering
Pharmacological approach• Driving cells to maturation via
ligands targeting its receptors;• Using drugs to promote a more
beneficial local environment to favor stem cells survival and differentiation
Conclusions
patents: 2009156521, EP 1807701, IT/MI2010A002037, PCT/IB20 11/054865, E0084789 RD 2012 04 24
sponsors: Fondazione Italiana Sclerosi Multipla, Cariplo Foundation, Italian MinisteroEuropean Commission ERANET NEURON projects
Maria P. Abbracchio, Professor and Lab HeadStefania Ceruti, Assistant ProfessorMarta Fumagalli, Assistant ProfessorDavide Lecca, Senior Research FellowChiara Parravicini, Research FellowMarta Boccazzi, Research FellowGianluca Menichetti, Research FellowElisabetta Bonfanti, Research FellowGiusy Coppolino, PhD studentDavide Marangon, PhD studentGiulia Magni, Research Fellow
Milano- 15 marzo 2017
Laboratory of Cellular and Molecular Pharmacology of Purinergic TransmissionDept Pharmacological and Biomolecular Sciences
University of Milan, Italy