Stem cells for brain cures

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1 13-14/11/2006, Istituto Superiore di Sanità Rome, Italy Frontiers in Imaging Science: High Performance Nuclear Medicine Imagers for Vascular Disease Imaging (Brain and Heart) Stem cells for brain cures GB Boncoraglio - EA Parati Unità Clinico Sperimentale Malattie Cerebrovascolari Fondazione IRCCS Istituto Nazionale Neurologico Carlo Besta - Milan, Italy

Stem cells for brain cures GB Boncoraglio - EA Parati Unità Clinico Sperimentale

2 Stem Cells: definition Stem cells are better defined as cells with certain biological functions rather than discrete cellular entities; Stem cell play a physiological role from embryogenesis to adulthood. Ref: Blau HM, Brazelton TR, Weimann JM. Cell 2001;105:

entities; Stem cell play a physiological role from embryogenesis

3 Stemness Properties Undifferentiated Features Self-Renewal capacity Multipotentiality Regenerate damaged tissues Ref: Potten CS, Loeffler M. Development 1990;110: ; Lagasse E. et al. Immunity 2001;14: ;

damaged tissues Ref: Potten CS, Loeffler M.

4 Models of brain damage Focal damage of a specific cell line: Parkinson's disease, amyotrophic lateral sclerosis, Focal damage of all the cell lines: stroke Diffuse brain damage: Alzheimer's disease

5 Stroke: brain penumbra diffusion/perfusion mismatch final lesion volume hours days-weeks Ref: Albers GW. Stroke 1999;30:

6 Stroke: molecular penumbra Ref: Sharp FR et al. J Cereb Blood Flow Metab 2000;20:

7 Acute cerebral ischemia: angiogenesis Activation of endothelial cells and glia occurs at least 2 days after ischemia, and capillary buds form by 7 days. Microvascular density, which relates to newly formed vessels, correlates with the survival time after the onset of ischemic stroke. Ref: Marti HJ et al. Am J Pathol 2000;156: ; Krupinski J et al. Stroke 1994;25:

Microvascular density, which relates to newly formed vessels, correlates with the survival

8 Angiogenetic factors The penumbra suffers from hypoxia and responds with an angiogenic reaction: proliferating endothelial cells and new vessels originate from the penumbra and invades the ischemic core. This physiological response may be enforcing by exogenous stimulation with angiogenetic factors. Ref: Marti HH, Risau W. Thromb Haemost 1999;82S1:44-52.

9 Neurogenic areas in adult CNS 1. Exist! 2. Are located in: Olfactory bulb; Subventricular zone; Subgranular zone of the dentate girus in the hippocampus.

10 Neurogenesis in adult rats after MCAO

11 Neuroangiogenic recruitment mechanisms Ref: Palmer TD, Willhoite AR, Gage FH. J Comp Neurol 2000;425:

12 In situ and systemic stem cells transplantation for stroke Graft Source Cell Type Comments Lateral ganglionic eminence Neural progenitor cells Postmitotic, neuron-like cells Immortalized neural stem cells Bone marrow stromal cells Human umbilical cord blood cells Porcine, striatal progenitor Rat, embryonic neural progenitor Cultured, postmitotic neurons Transformed hippocampal stem cell line Stromal cells from bone marrow Stem cells from umbilical cord Grafts differentiate into neurons and glia, elaborate extensive processes in focal model Differentiate into all brain cell types in focal model Safety established at 12 mo after transplant in human stroke trial Transplants contralateral to lesions may improve recovery in focal model Benefit may be related to release of trophic factors in focal model Benefit may be related to release of trophic factors in focal model Ref: Savitz SI, Caplan LR et al. Ann Neurol 2002;52:

Stromal cells from bone marrow Stem cells from umbilical cord Grafts differentiate into neurons and glia, elaborate extensive processes in focal model Differentiate into all brain cell types in focal

13 Non-circulating bone marrow mesenchymal stem cells Ref: Chopp M, Li Y. Lancet Neurol 2002;1:92-100

14 Adult circulating stem cells: multipotentiality and plasticity Ref: Blau HM, Brazelton TR, Weimann JM. Cell 2001;105:

15 CD34 + cell transplantation enhances neurogenesis through neovascularization in stroke-injured brain Peterson DA: Umbilical cord blood cells and brain stroke injury: bringing in fresh blood to address an old problem. J Clin Invest 2004;114:

Umbilical cord blood cells and brain stroke injury: bringing

16 rhg-csf in stroke patients Increased angiogenesis in the penumbra and vascular healing; Neuroprotection and reduction of apoptosis; Restoration of neuronal damage and synaptogenesis. Schneider A, Schabitz WR et al.: The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 2005;115:

synaptogenesis. Schneider A, Schabitz WR et al.

17 Magnetodendrimers as a new class of cellular MR contrast agents Bulte JW et al.: Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol 2001;19:

18 In vivo tracking of stem cells Bulte JW et al.: Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol 2001;19:

STEM CELL FELLOWSHIP

STEM CELL FELLOWSHIP Module I: The Basic Principles of Stem Cells 1. Basics of Stem Cells a. Understanding the development of embryonic stem cells i. Embryonic stem cells ii. Embryonic germ cells iii. Differentiated stem cell