Pascale V Guillot, Associate Professor at University College London, investigates the possibility of exosome therapy for those living with brittle bone disease
Brittle bone disease, also called osteogenesis imperfecta manifests by a fragile skeleton that breaks easily. Whilst the severity of this congenital condition varies from mild to severe, some babies do not survive the neonatal period. Brittle bone disease also manifests by skeletal malformation and people with the disease are affected for life as there is no current treatment.
The disease develops because of genetic modifications in the DNA coding for type I collagen, which is the main component of the bones. As a result, the bone extracellular matrix is very weak. Healthy bones constantly remodel, with new bone being formed and old bone being degraded. This very fragile balance ensures that the skeleton remains strong and healthy.
This is particularly important because, in addition to holding the body and protecting internal organs, bones also have the function of being a reservoir of important factors that are released on demand. When the balance of bone formation – bone degradation is altered, more bone is being degraded than formed and this process contributes to fragilise the skeleton. This may happen for various reasons, including malnutrition, inactivity, or changes in hormone levels. In the case of brittle bone disease, this happens because of a mistake in the DNA.
As a result, people with brittle bone disease do not form much bone matrix and the bone matrix formed contains a defective type I collagen molecule, which overall renders the bones brittle.
Cell therapy for brittle bone disease
We have shown that mesenchymal stem cells isolated from healthy donors are capable of counteracting bone fragility. Following transplantation, donor mesenchymal stem cells were found to have been incorporated in almost all the organs but were found in higher concentration at the sites of bone formation.
However, the amount of donor cells remained too low to explain the two-third reduction in the long bone fracture rate that was observed. In addition, despite using donor cells specialised in bone-forming cells once they reached bones, it remained difficult to show that they significantly contributed to increasing the amount of bone formed. Instead, mesenchymal stem cell transplantation contributed to improving the health of the bone extracellular matrix.
Despite promising results, mesenchymal stem cell therapy is based on the injection of live cells originating from a donor with different genetic landscapes.
How do stem cells work?
The exact mode of action of stem cells remains to be elucidated. In addition to differentiating into specialised cell types, mesenchymal stem cells have been shown to possess anti-inflammatory properties. Experiments based on co-culture of mesenchymal stem cells with target cells in the absence of cell contact between both populations have shown that mesenchymal stem cells have the potential to modulate the inflammatory state of target cells through the release of anti-inflammatory factors.
The ability of mesenchymal stem cells to stimulate the repair of diseased tissues without directly contributing to tissue formation is called a paracrine effect. But how are these effects mediated?
Exosomes instead of mesenchymal stem cells?
Exosomes are tiny sacks that are released from cells and that enable cells to communicate with each other. Their size is around 30-150 nm in diameter and they are released in the extracellular space. They contain important factors such as proteins, mRNA, RNA and DNA, that are involved in modulating the behaviour of the cells that integrate them (also called target cells). Exosomes are especially interesting in the field of regenerative medicine because there is some experimental evidence for their ability to mediate the paracrine effects of mesenchymal stem cells. It has long been hypothesised that stem cells were able to regenerate tissues through direct differentiation (or specialisation) into a specific cell type and replace damaged cells with new ones.
However, evidence suggests that instead, stem cells mediate their repair capacity indirectly, by influencing how target cells in their surroundings behave, which stimulates the endogenous repair capacity of tissues. The cargo of the exosomes released by mesenchymal stem cells can enter target cells to alter the function of their genes or to provide proteins that will alter specific pathways.
As exosomes are released by mesenchymal stem cells in the extracellular space, they can be isolated from the culture media of the cells and stored in freezers for a long time without losing their characteristics and their potential to influence target cells. It is also possible to modify the cargo of exosomes to incorporate additional proteins or drugs to be delivered to target cells.
Exosomes for the treatment of brittle bone disease
Exosome therapy presents several advantageous characteristics compared to live cell therapy. Exosomes are not alive, and although they have the capacity to migrate to a variety of target cells, they are not engrafting in target tissues and not contributing to tissue formation. In addition, it is possible to engineer exosomes to direct them to specific target cell types and modify their cargo to deliver proteins of interest.
Therefore, mesenchymal stem cell-derived exosomes are not envisaged as an innovative approach to counteract bone fragility and improve skeletal health. This principle can also be applied to other pathologies characterised by bone fragility such as osteoporosis. Finally, exosomes can easily be injected through the blood circulation. Together, exosome therapy can deliver regenerative factors directly to the bones for the long-term improvement of skeletal health.
(1) Guillot, P. V. et al. Intrauterine transplantation of human fetal mesenchymal stem cells from first-trimester blood repairs bone and reduces fractures in osteogenesis imperfecta mice. Blood 111, 1717–1725 (2008).
(2) Ranzoni, A. M. et al. Counteracting bone fragility with human amniotic mesenchymal stem cells. Sci Rep 6, 39656 (2016).
(3) Ranzoni, A. M., Corcelli, M., Arnett, T. R. & Guillot, P. V.
Micro-computed tomography reconstructions of tibiae of stem cell transplanted osteogenesis imperfecta mice. Sci Data 5, 180100 (2018).
(4) Vanleene, M. et al. Transplantation of human fetal blood stem cells in the osteogenesis imperfecta mouse leads to improvement in multiscale tissue properties. Blood 117, 1053–1060 (2011).
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