Nanobodies to prevent hematopoietic stem cell bias and hyper-inflammation.

With a growing ageing population, there is an imminent demand to develop new therapeutic strategies to ameliorate disorders of the hematopoietic system. Our innate immune system can remember its previous encounters with inflammatory triggers.

Epigenetic memories of previous inflammatory experiences throughout an individual's lifetime are imprinted in hematopoietic stem cells (HSCs), a small pool of bone marrow progenitors that give rise to all our blood cells. Inflammation harms HSCs causing their functional decline and premature ageing.

It also causes long-term differentiation bias, and a heightened basal inflammatory status, known as “inlfammageing”.

The most striking characteristic of aged HSCs is their increased expression of platelet and megakaryocyte markers and their commitment towards platelet biogenesis, referred to as “Platelet-bias."" Platelet bias has important consequences to human health.

In our ERC starting grant project PLAT-IL-1 (714175), we discovered that platelets boost the inflammatory capacity of innate immune cells and are essential for the cytokine production of human monocytes.

Our findings support that a dangerous combination of myeloid and platelet bias in inflammation-exposed HSCst results in a heightened innate immune activation.

The injuries to HSCs are persistent and continue even after the clearance of the inflammatory insult, indicating that remnants of inflammatory events accrue and prolong damage to HSCs.

Hence, if we could “erase"" these harmful remnants, we could UNBIAS HSCs differentiation and prevent hyper-inflammation. In our ERC-funded project, we developed novel nanobodies that efficiently eliminate remnants of inflammation in vivo.

In this PoC project, we will test the ability of nanobodies to erase memories from previous inflammatory events and prevent hyper-inflammation. This project will be a stepping stone to licensing our nanobodies to industrial partners.