Stromal dysfunction and neuroinflammation - experimental and clinical studies

We will combine our 20-year knowledge on the immunomodulatory properties of mesenchymal stromal cell (MSC) transplantation with results from 2 separate projects on neuroinflammation, i.e. multiple sclerosis (MS) and fatigue/cognitive dysfunction after hematopoietic stem cell transplantation (HSCT).We believe that stroma – immune – neuronal crosstalk is defective and that activated perivascular stroma in the CNS is deficient in trophic signals, secretes profibrotic matrix molecules and cytokines that propagate neuroinflammation.

In MS, we will continue our characterization of fibrotic perivascular stroma of brain tissue and MSC from MS patients.After HSCT, we have identified patients with cognitive dysfunction, hypoactivation of the prefrontal cortex and decreased immune regulatory proteins and immune subsets in the CNS.

We believe that deficiency of trophic signals from the perivascular stroma activate microglia and alloreactive T-cells in the CNS and disrupt synaptic function.In transgenic mice where transcription factor Ebf2 is GFP marked and Ebf2-CreER x Rosa26-DTA mice where MSC can be selectively eliminated by Tamoxifen, we will induce neuroinflammation and study the stroma in the early inflammatory events.

Possible reversal of neuroinflammation will be studied after intranasal adoptive transfer of MSC.It is not until we understand the respective contributions of stroma, immune subsets and neurons that we can design targeted therapies in various neuroimmune disorders.