STROKECELLFUSION · Cell fusion as regenerative tool for stroke treatment
FP7 — People (Marie Curie Actions)
- Duration
- 2010-07-01 → 2012-06-30
- EU contribution
- €152,917
- Participants
- 1
- Scheme
- MC-IEF
Lines connect the coordinator with its partners.
Results in brief
Cell fusion as regenerative tool for stroke treatment
Ischemic stroke ranks among the leading cause of death and adult disability in developed countries. Upon an ischemic insult, an area called penumbra area is formed, which, although at risk, is still possible to recover. It was reported that bone marrow transplantation made 24hrs after the stroke leads to functional outcome. Cell fusion is one of the underlying mechanisms, but its true regenerative potential is hindered by the low frequency of fusion events, especially in the brain. StrokeCellFusion describes a strategy based in the co-administration of bone marrow derived cells (BMSCs) and the controlled release of fusogenic factors aimed to increase cell fusion events. Therefore, the objectives of the present project are: 1) identify new putative fusogenic factors in vitro; 2) develop a nanocarrier adequate for the sustained and controlled delivery of the selected fusogenic factors; 3) evaluate the in vivo efficacy of the developed system in a mouse model of stroke. From the developed nanocarriers poly(lactic) nanoparticles (PLA NPs) were the drug delivery system selected. PLA NPs were not cytotoxic, exhibited the physical/chemical properties and the release profile more appropriates for the current biomedical application. Furthermore, biodistribution studies of PLA NPs labeled with fluorophore rhodamine (Rho) revealed an overall body distribution and were not concentrated in kidney/liver. With the help of an in vitro cell fusion detection system and FACS analysis, interleukine-4 (IL-4) was indentified and selected as a putative fusogenic agent, as it increased the fusion events between neural cells with BMSCs. Later on, it was assessed the in vivo effect of IL-4 intracerebral administration in animals transplanted with BMSCs. Mice were sacrificed 15 days after IL-4 administration and it was observed a slight increase in the number of fused cells in comparison with sham control. However, under pathological conditions, such as stroke, the fusogenic effects of IL-4 might be potentiated due to the unique environment generated at the infracted area. Furthermore, it was confirmed that IL-4 effect was not due to the recruitment of activated microglia. The next step would be to test the effect of co-administrating IL4-loaded NPs together with intravenous bone marrow transplant in the mouse model of stroke. In summary, in StrokeCellFusion it was developed a delivery system that can be applied to other neurodegenerative conditions that involve the destruction/alteration of the blood brain barrier and that require a drug with a controlled pharmacokinetic profile. Furthermore, IL-4 has been identified as a fusogenic factor with potential to increment fusion events up to effective levels for therapy.
Data: CORDIS, © European Union
Project objective
In the last years it has been shown that transplanted adult bone marrow derived stem cells (BMSCs) have the ability to fuse with cells of other types and restore several pathologies such as congenital liver failure and muscular dystrophy. On the nervous system, it was recently reported that bone marrow transplantation (BMT) made 24 hours after the stroke leads to a functional outcome. Cell fusion is one of the underlying mechanisms as it has been shown that it is indirectly implicated in the formation of vasculature after stroke. Thus, stroke is a pathology susceptible to be treated with this cell therapy mechanism. Despite the great potential of this mechanism of regeneration, the low frequency of fusion events, especially in the brain, has veiled and hindered the true regenerative potential of cell fusion. Therefore, the main objective of this project is to identify fusogenic factors that will increase cell fusion events to an effective level for cell therapy of neurological disorders. For this, firstly we will screen in vitro new putative fusogenic with the help of an in vitro cell fusion detection system and FACS analysis. Later, chitosan nanoparticles will be developed for the controlled release of the putative fusogenic factors. Finally, we will evaluate the in vivo efficacy of these factors trough a series of intravenous BMT co-administered with nanoparticles loaded with the selected factors in the mouse model of stroke. We will correlate an increment in the cell fusion events with the putative improvement in stroke symptoms. With this project we will improve our knowledge about adult stem cell plasticity and explore cell fusion process as a neuroregenerative process for the treatment of stroke.
Original text from CORDIS.
Participants
- AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS · MadridCoordinatorSpain
Links
Data: CORDIS, © European Union