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Les accidents vasculaires cérébraux (AVC) représentent l’une des premières causes de morbi-mortalité dans les pays industrialisés et sont en constante augmentation. Pour l’heure, aucune autre thérapie que la thrombolyse intraveineuse n’est validée, or moins de 10% des patients y sont éligibles.Les premiers essais de thérapie régénérative par greffe de progéniteurs endothéliaux ont montré leur efficacité au niveau préclinique sur la récupération fonctionnelle, mais très peu de cellules parviennent jusqu’au site de la lésion pour y exercer leurs effets. De précédents travaux ont montré que l’érythropoïétine (EPO) augmentait la mobilisation et la prolifération de progéniteurs endothéliaux depuis la moelle osseuse, ainsi que leur adressage vers les sites ischémiés in vivo.Nous avons formulé l’hypothèse que l’EPO pouvait permettre aux progéniteurs endothéliaux vrais (ECFCs) d’atteindre le site ischémié en plus grand nombre pour y exercer un effet plus important, plus rapidement. Nous avons donc décidé d’évaluer trois stratégies d’optimisation : coadministration d’ECFCs et d’EPO, administration d’ECFCs prétraités à l’EPO, et enfin coadministration d’ECFCs et d’un dérivé de l’EPO dénué d’effet hématopoïétique. Pour nos derniers travaux, nous nous sommes aidés de l’imagerie isotopique µSPECT/CT pour quantifier l’adressage au niveau de la lésion des ECFCs avec ou sans optimisation pharmacologique à l’EPO, et évaluer longitudinalement leurs effets bénéfiques sur la rupture de la barrière hémato-encéphalique, l’apoptose cérébrale et le débit sanguin cérébral résiduel, en complément des techniques référentes et de l’évaluation clinique neurofonctionnelle. / Stroke represents a leading cause of morbidity and mortality in industrialized countries and prevalence steadily increases. For now, no other therapy that intravenous thrombolysis is validated, still, less than 10% of patients are eligible.The first preclinical regenerative therapy trials using endothelial progenitor cells engraftment gave evidence of their efficacy on functional recovery, although very few cells reached the site of injury to exert their effects are. Previous works showed that erythropoietin (EPO) increased mobilization and proliferation of endothelial progenitor cells from bone marrow, as well as their homing to the ischemic sites in vivo.We hypothesized that EPO could enable true endothelial progenitor cells (ECFCs) to reach the ischemic site in larger quantity, faster, to exercise a greater effect. We decided to evaluate three optimization strategies: coadministration of ECFCs and EPO, administration of EPO-pretreated ECFCs, and finally coadministration of ECFCs and an EPO derivative devoid of hematopoietic effect.In this work, we used μSPECT/CT imaging to quantify the ECFCs homing to the ischemic site with or without EPO optimization after cerebral ischemia, and longitudinally assessed their beneficial effects on blood-brain barrier disruption, cerebral apoptosis and residual cerebral blood flow, complementary to the referent techniques and neurofunctional clinical evaluation.

Background: Haematotoxicity of conventional chemotherapies often results in delays of treatment or reduction of chemotherapy dose. To ameliorate these side-effects, patients are routinely treated with blood transfusions or haematopoietic growth factors such as erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF). For the latter ones, pharmaceutical derivatives are available, which differ in absorption kinetics, pharmacokinetic and -dynamic properties. Due to the complex interaction of cytotoxic effects of chemotherapy and the stimulating effects of different growth factor derivatives, optimal treatment is a non-trivial task. In the past, we developed mathematical models of thrombopoiesis, granulopoiesis and erythropoiesis under chemotherapy and growth-factor applications which can be used to perform clinically relevant predictions regarding the feasibility of chemotherapy schedules and cytopenia prophylaxis with haematopoietic growth factors. However, interactions of lineages and growth-factors were ignored so far. Results: To close this gap, we constructed a hybrid model of human granulopoiesis and erythropoiesis under conventional chemotherapy, G-CSF and EPO applications. This was achieved by combining our single lineage models of human erythropoiesis and granulopoiesis with a common stem cell model. G-CSF effects on erythropoiesis were also implemented. Pharmacodynamic models are based on ordinary differential equations describing proliferation and maturation of haematopoietic cells. The system is regulated by feedback loops partly mediated by endogenous and exogenous EPO and G-CSF. Chemotherapy is modelled by depletion of cells. Unknown model parameters were determined by fitting the model predictions to time series data of blood counts and cytokine profiles. Data were extracted from literature or received from cooperating clinical study groups. Our model explains dynamics of mature blood cells and cytokines after growth-factor applications in healthy volunteers. Moreover, we modelled 15 different chemotherapeutic drugs by estimating their bone marrow toxicity. Taking into account different growth-factor schedules, this adds up to 33 different chemotherapy regimens explained by the model. Conclusions: We conclude that we established a comprehensive biomathematical model to explain the dynamics of granulopoiesis and erythropoiesis under combined chemotherapy, G-CSF, and EPO applications. We demonstrate how it can be used to make predictions regarding haematotoxicity of yet untested chemotherapy and growth-factor schedules.:Background; Methods; Results; Model predictions; Discussion; Conclusions

BACKGROUND:Diffuse axonal injury is a common consequence of traumatic brain injury (TBI) and often co-occurs with hypoxia, resulting in poor neurological outcome for which there is no current therapy. Here, we investigate the ability of the multifunctional compound erythropoietin (EPO) to provide neuroprotection when administered to rats after diffuse TBI alone or with post-traumatic hypoxia.METHODS:Sprague-Dawley rats were subjected to diffuse traumatic axonal injury (TAI) followed by 30minutes of hypoxic (Hx, 12% O2) or normoxic ventilation, and were administered recombinant human EPO-alpha (5000IU/kg) or saline at 1 and 24hours post-injury. The parameters examined included: 1) behavioural and cognitive deficit using the Rotarod, open field and novel object recognition tests / 2) axonal pathology (NF-200) / 3) callosal degradation (hematoxylin and eosin stain) / 3) dendritic loss (MAP2) / 4) expression and localisation of the EPO receptor (EpoR) / 5) activation/infiltration of microglia/macrophages (CD68) and production of IL-1beta.RESULTS:EPO significantly improved sensorimotor and cognitive recovery when administered to TAI rats with hypoxia (TAI+Hx). A single dose of EPO at 1hour reduced axonal damage in the white matter of TAI+Hx rats at 1day by 60% compared to vehicle. MAP2 was decreased in the lateral septal nucleus of TAI+Hx rats / however, EPO prevented this loss, and maintained MAP2 density over time. EPO administration elicited an early enhanced expression of EpoR 1day after TAI+Hx compared with a 7-day peak in vehicle controls. Furthermore, EPO reduced IL-1beta to sham levels 2hours after TAI+Hx, concomitant to a decrease in CD68 positive cells at 7 and 14days.CONCLUSIONS:When administered EPO, TAI+Hx rats had improved behavioural and cognitive performance, attenuated white matter damage, resolution of neuronal damage spanning from the axon to the dendrite, and suppressed neuroinflammation, alongside enhanced expression of EpoR. These data provide compelling evidence of EPO's neuroprotective capability. Few benefits were observed when EPO was administered to TAI rats without hypoxia, indicating that EPO's neuroprotective capacity is bolstered under hypoxic conditions, which may be an important consideration when EPO is employed for neuroprotection in the clinic.

Skeletal muscle is a major organ comprising 30-40% of the human body mass. The coordination of processes resulting in mature muscle requires many genes, and their loss can result in debilitating muscle disorders. Of the strategies being developed to cure muscle diseases, enhancement of the natural process of muscle cell fusion in existing or introduced myogenic cells has great therapeutic potential. In this work, we determined whether a drug that stimulates proliferation and fusion of myoblasts could alleviate murine Duchenne muscular dystrophy. We also studied the necessity of a gene that is upregulated in early fusing human myoblast cultures and its role in muscle disease development.

Erythroid terminal differentiation couples sequential cell divisions with progressive reductions in cell size. The erythropoietin receptor (EpoR) is essential for erythroblast survival, but its other functions are not well characterized. I used Epor−/− mouse erythroblasts endowed with survival signaling to identify novel non-redundant EpoR functions. I found that, paradoxically, EpoR signaling increases red cell size while also increasing the number and speed of erythroblast cell cycles. Specifically, I found that high levels of EpoR signaling increase the size and shorten the cycle of early erythroblasts, which are amongst the fastest cycling somatic cells. I confirmed the effect of erythropoietin (Epo) on red cell size in human volunteers, whose mean corpuscular volume (MCV) increases following Epo administration. Our work shows that EpoR signaling alters the expected inverse relationship between cell cycle length and cell size. Further, diagnostic interpretations of increased MCV should now include high Epo levels and hypoxic stress. The ability of EpoR signaling to increase cell size in rapidly cycling early erythroblasts suggests that these cells have exceptionally efficient EpoR-driven mechanisms for growth. I found evidence for this in ongoing work, where Epor−/− and Stat5−/− single-cell transcriptomes show dysregulated expression of ribosomal proteins and rRNA transcription and processing genes. Global rates of ribosomal rRNA transcription and protein synthesis increase in an EpoR dependent manner during a narrow developmental window in early ETD, coincident with the time of cell cycle shortening. Our work therefore suggests EpoR-driven regulation of ribosome biogenesis and translation orchestrating rapid cycling and cell growth during early ETD.

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