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Multi-potent adult progenitor cells to treat stroke

Final Report Summary - STROKEMAP (Multipotent Adult Progenitor Cells to treat Stroke)

Stroke is caused by the occlusion of an artery providing oxygen to the brain, resulting in irreversible brain tissue damage for which there is no curative treatment available as yet. Each year, approximately 1 million people suffer strokes in the European Union. Approximately 25 % of men and 20 % of women experience a stroke if they live to 85 years, and stroke is the second most common cause of death worldwide.

The hypothesis underlying the Specific Targeted Project (STREP) STROKEMAP was that a universal population of stem cells that can both restore blood-flow through the ischemic brain region and can differentiate in vivo into neurons and astrocytes that died due to cerebral ischemia will be the superior cell population for vascular and neural repair needed for therapy of stroke. The overall hypothesis was that allogeneic Multipotent adult progenitor cells (MAPCs), a novel bone marrow stem cell population first described by the Verfaillie lab in 2002, are an ideal candidate stem cell population as they could generate endothelial cells and smooth muscle cells needed to restore the vasculature, and rodent MAPC could generate neuro-progenitors suitable to restore neural circuitry.

The proposed studies and objectives were to perform:
1. studies to further our understanding in processes that underlie the differentiation and specialisation of human and rodent ll/IAPC to endothelial cells and neural cells;
2. to compare the efficacy of MAPC or their differentiated progeny with gold-standard cell populations (that is bone marrow cells currently used in animal models) to restore circulation and neural circuitry damaged by stroke;
3. to develop innovative non-invasive imaging techniques that will allow us to follow cell survival, migration and engraftment following transplantation as well as to obtain insights in the mechanisms) through which stem cells repair the blood supply and neural circuitry in the brain and provide quantitative assessment of such repair;
4. to develop strategies that will allow transplantation of universal donor human stem cells and develop strategies to circumvent possible immunological rejection;
5. to develop an ethical / legal framework in which to initiate clinical trials with stem cells for stroke;
6. to develop clinical scale and grade stem cell populations, that could be used in clinical trials upon completion of the translational and preclinical studies proposed in this project.

To accomplish these tasks, STROKEMAP assembled a team of investigators from five European countries, an SME (ReGenesys BVBA, Belgium) and an industrial partner (Guerbet, France) with complementary expertise.

The project was divided in several work programmes, including:
(1) basic stem cell biology;
(2) stem cell transplantation in ischemic brain;
(3) immunology of stem cells;
(4) noninvasive imaging of stem cells grafts and their effect on ischemic brain;
(5) development of a legal-ethical framework for stem cell banking; and a last program on
(6) clinical grade production of stem cells.

Work programme 1: Stem cell biology
The aims here were to further characterise the differentiation potential of MAPC towards arterial endothelium, and identify key regulators of the differentiation process, and to evaluate the ability of MAPC to generate neural cells and evaluate (vascular niche-derived) signals that enhance this differentiation.

Work programme 2: Stem cell transplantation in ischemic brain

In this program, the effect of undifferentiated and lineage-committed rodent MAPC on stroke in rodent brain would be evaluated, and human MAPC in immunodeficient mouse models of stroke.

Work programme 3: Immunology of MAPC
ln this work programme, the immunological impact of murine and human MAPC, using in vitro and in vivo assays would be assessed.

Work programme 4: Noninvasive imaging techniques to evaluate the fate of MAPC and the effect of MAPC on endogenous neural stem cells and vasculature

Work programme 5: Framework to develop clinical grade stem cell products in an ethically responsible manner
In this programme a framework was to be examined to develop clinical grade stem cell products in an ethically responsible manner.

Work programme 6: Generation of clinical grade human MAPC
In this work programme standard operating procedures and methods to large scale produce human MAPC and if needed differentiated progeny would be developed.

Exploitable knowledge

- Vascular / lymphatic endothelial cells
- Superior immunomodulation by human MAPC
- Superior vascular and tissue repair by MAPC in limb ischemia model
- Superior vascular and tissue repair by MAPC in MCAO model

Exploitable product(s) or measure(s)

- Vascular / lymphatic endothelial cells
- Clinical grade multistem for aGVHD prevention and cGVHD therapy
- Clinical grade multistem for critical limb ischemia
- Clinical grade ivlultistem for vascular stroke.