le donne nelle stem - esperienza...

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

Wikimedia Italia


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


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


Extent of the problem: the case of Alzheimer’s

disease


…not only Alzheimer’s….


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.


The promise of stem cells for neuro-rejenerative therapies

Embryonic cells transplantation for cell substitution therapyin Parkinson’s, Alzheimer’s, multiple sclerosis, ALS, stroke…


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!


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


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


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


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


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Gelosa P et al., submitted 2016


GPR17 is also a new target to implement cognitive functions


Marschallinger J et al., Nature Communications, 2015


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


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


Laboratory of Cellular and Molecular Pharmacology of Purinergic TransmissionDept Pharmacological and Biomolecular Sciences

University of Milan, Italy

le donne nelle stem - esperienza...

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