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FRIMEDBIO-Fri med.,helse,biol

Immune-driven regeneration: harnessing regulatory T cells to enhance the efficacy of mesenchymal stem cell-based bone regeneration

Alternative title: Immunstyrt regenerasjon: utnyttelse av regulatoriske T-celler for å øke effekten av mesenchymal stamcelle basert beinregenerasjon

Awarded: NOK 8.0 mill.

Millions of people visit hospitals worldwide annually to receive bone grafts to treat bone diseases and defects. This raises a huge burden on any society. The discovery of stem cells, which are special cells from which all other functional cells are produced, has been a revolution in the bone regeneration field. For decades, stem cells, especially the ones in the bone marrow, have been successfully expanded in the laboratory and combined with safe materials to reconstruct bone defects that cannot heal on their own. However, researchers have struggled to establish this as a standard therapy in the clinic. One of the reasons behind that is that these stem cells when implanted interact with the recipient’s immune system and this impacts the success of the therapy. These interactions are largely unexplored and not understood. Therefore, our project was designed to help understand the role played by the immune system in the regeneration process after implanting stem cell-based therapies. This will be done by focusing on one of the immune cells, namely regulatory T cell, which has recently shown an unexplored critical potential on regeneration. We aim to unravel their molecular crosstalk with the implanted stem cells for bone regeneration. This functional crosstalk between the cells will be utilized to advance current stem cell expansion conditions and to design next generation regenerative therapies. This project brings together internal expertise and methodology in different fields from an outstanding network of international and national collaborators. We aim to produce knowledge to advance therapies that translate to positively impact healing of patients with clinically challenging bone defects. This project may also have wider implications for patients with compromised healing in tissues other than bone.

Critical sized bone defects present with a clinical challenge to date. Bone tissue engineering introduced the in vitro expansion of bone marrow-derived mesenchymal stem cells (BMSC) combined with biomaterials to reconstruct clinically challenging defects. Transplanted BMSC encounters a myriad of interactions with the recipient's immune system that affect the efficacy of the therapy. A particular subset of the adaptive immunity, regulatory T cells (Treg), has gained interest due to their critical potential on endogenous regeneration, which remains unexplored. We hypothesise that the interplay between the host immune system and the implanted BMSC to be centred around the Treg and BMSC cross-talk. There is a clear knowledge gap in the role of Treg in bone regeneration. By deciphering the molecular mechanisms to explain how Treg functionally regulates BMSC and their precise roles in bone regeneration, we will bridge this gap. This understanding will be translated into clinically relevant and novel cell-based therapeutics for bone regeneration. STEMreg aims to elucidate the functional impact of Treg on BMSC and harness the translational potential of this cross-talk using functionalised delivery systems in vivo. Bringing together internal expertise and methodology in different fields from an outstanding network of international and national collaborators we aim to achieve this goal through the following work packages: WP1. characterise the impact of Treg on BMSC and dissect the molecular mechanisms by which Treg controls the fate of BMSC; WP2. introducing Treg capacities as a BMSC priming strategy in optimised xenogeneic-free expansion, WP3. assessing the importance of endogenous Treg in the efficacy of the BMSC construct in vivo, WP4. harnessing endogenous Treg to promote BMSC-based bone regeneration in vivo.


FRIMEDBIO-Fri med.,helse,biol