No treatment for traumatic brain injury (TBI) patients has yet provided prolonged neurorestorative effects. Sustained TBI-induced neuroinflammation (NI) is associated with poor outcomes and a growing body of evidence suggests a link between NI and post-TBI neurodegenerative disorders (ND). Thus, modulation of NI offers a promising therapeutic window for interventions aimed at improving the prognosis of TBI. In this context immunomodulation (IM) via mesenchymal stromal cell (MSC)-based therapies have been investigated in various animal models of brain injury and are currently investigated in human to treat various ND through NI modulation but not yet in the specific setting of TBI. These data shown good safety record. In this human multi-centre double-arm double-blind placebo randomized study, we hypothesize that iterative IV injection of Wharton's jelly of the umbilical cord (WJ-UC-MSC) prevents NI and brain lesions exacerbation through IM and thus improve neuroclinical status. We will include 68 patients with severe TBI (Glasgow score<12 within the 48 first hours, brain lesion on CT scan, need for intracranial pressure monitoring) unresponsive to verbal commands 5 days after sedation discontinuation. They will be randomized to receive either 3 injections 1 week apart of WJ-UC-MSC or placebo. Primary outcome will be NI quantified by [18F]-DPA-714 signal intensity measured by dynamic quantitative PET-MRI at 6 months. A clinical evaluation will be performed at 6 and 12 months. We also plan to study early immune response to WJ-UC-MSC using deep immunophenotyping (flow cytometry analysis), next generation sequencing and digital PCR, on blood samples performed between first and second injection. Finally, we will seek for predictive biomarkers by studying transcriptomic and epigenomic peripheral blood mononuclear cells phenotype, on blood samples performed before first and third injections and at 6 months, in order to implement post-TBI personalized medicine.