STEMMED

Stroke (80% are ischemic) is the leading cause of disability. The societal cost linked to disability represents 42% of the total cost of stroke (8.3 billions of Euros per year in France). The only available therapy is thrombolysis which must be applied within the 4.5h after stroke onset. Only 2% of stroke patients can be thus treated. In the chronic phase, only rehabilitation programs improve functional recovery. Thus, the subacute phase represents an interesting target for limiting ongoing cell death in the penumbra and stimulating endogenous repair mechanisms. Cell therapies based on stem cells (SC) are currently developed for this purpose. Numerous experimental studies showed an improvement of recovery after SC administration during the acute phase (first 24h). However, a therapy applicable after several days or weeks following stroke could concerned a lot of patients. Few studies deal with SC therapy during this subacute phase. Partner 1 is leading a phase II clinical trial to assess the safety and tolerance of SC therapy in stroke patients using autologous bone marrow-derived mesenchymal SC (hBM-MSC). Vascular remodeling, immune response and neurogenesis which spontaneously occur after ischemic stroke contribute to cerebral plasticity. However, these mechanisms and their time course are not fully understood, as well as the effect of SC on these. A better understanding of these mechanisms and their temporal evolution will contribute to SC therapy optimization for stroke._x000D_ Induced pluripotent stem cells (iPSC) constitute a new and attractive cell source for cell therapy in stroke. IPSCs possess the cardinal features of pluripotency and self-renewal which are assets for a large-scale and standardized production. IPSC allow the development of biobanks which might reduce the delay of treatment for stroke patients So far, the possibility to replace hBM-MSC by human iPSC-derived MSC (hiPSC-MSC) has not been investigated. The potential of hiPSC-MSC to reduce stroke-induced functional impairments remains to be determined._x000D_ The aims of our preclinical project are: 1) To assess and compare the impact of intravenous (IV) administration of hBM-MSC and hiPSC-MSC on vascular remodeling, immune response and neuronal proliferation after transient occlusion of the middle cerebral artery (MCAo) in rats; 2) To correlate these effects with functional recovery and data obtained in the ongoing clinical trial; 3) To translate these results to prepare a phase III clinical trial for IV hBM-MSC; 4) To pave the way to the use of hiPSC-MSC. _x000D_ For this collaborative project, state-of-the-art techniques will be combined: in vivo imaging (micro-SPECT, MRI, two-photon microscopy), behavioral tests, cellular and molecular biology. The hBM-MSCs have been chosen because Partner 1 has preliminary data showing improvements of recovery after IV administration in the subacute phase in a MCAo model with an effect on angiogenesis. HBM-MSCs have been shown to be non carcinogenic. One will continue to pay great attention to this point all along the project, notably for hiPSC-MSC. Partner 2 has provided the proof-of-concept of using hiPSC as a cell source for SC therapy in stroke. _x000D_ Partners 1,2 and 3 have experience in stroke and SC research with complementary scientific and technical expertise. Partner 4 (Ectycell) is the European leader for human embryonic SC production and is actively developing a hiPSC sector for the production of differentiated progenies, including hiPSC-MSC.