As you may know from this blog, host conditioning is required for successful engraftment of hematopoietic stem cells in BMT models. Conditioning allows to prep bone marrow niche for donor stem cells by depleting host stem/ progenitor cell pool. A typical niche conditioning in BMT models (as well as in clinic) is done by total body irradiation (TBI). Besides TBI, antibody- and chemotherapy- based conditioning is also used in experimental models and in the clinic. Successful niche conditioning is a prerequisite of robust stem cell engraftment! But what about other than hematopoietic stem cells? Well, outside of hematopoietic system the picture is more complex. For some type of cells niche conditioning is required for engraftment, for others – not so much. A few examples:
- Conditioning with irradiation does not favor engraftment of MSC
- Experimental lethal irradiation does not enhance donor MSC engraftment
- Host conditioning with total lymphoid irradiation allows engraftment of embryonic stem cells
- Lymphodepletion conditioning increase efficacy of adoptive T-cell transfer
- Conditioning with bacterial pathogen enables engraftment of memory T-cells
The very recent study, published in Nature Medicine, applies the concept of niche conditioning by TBI to lung stem cells. Authors initial attempts to achieve meaningful engraftment of fetal lung cells in injury model were failing. When sublethal TBI was used 48 hours after injury, multilineage lung engraftment of donor cells was observed. The authors demonstrated as high as ~30% lung engraftment in mouse syngenic model and as low as ~3% of human fetal lung cell engraftment in xenogenic model. Mechanistically, post-injury TBI depleted competitive host-derived lung stem cells and, therefore niches were empty and prep’d for donor cells.
Results of this study expand our knowledge about potential use of TBI conditioning for engraftment of stem cells beyond hematopoietic system. The authors speculate, that analogously to BMT models, this approach may work for other sources of lung stem cells, such as iPS cells. It seem like this approach may work well for lung injury-repair models. I’d be curious to see something like this for digestive system injury models, since intestinal stem cells are highly proliferative and radiation-sensitive.
Reading this study, I’ve gotten few questions:
- What are the side effects of this sublethal TBI on hematopoietic system and other organs? If other systems are affected by TBI, how does it impact the engraftment and functional outcome? Should hematopoietic system (read immune system and blood) be boosted by bone marrow in parallel with lung cell transplant?
- What if lung cells were transplanted locally instead of intravenous delivery route?
- How will it work in the conditions where there is a deficiency of host lung stem cells (so you don’t need to prep niches)?
- From translational point of view, TBI is not good approach to prep a patient for lung cell therapy – too harsh and toxic. I wonder if there is a better niche conditioning method, specific for lungs. For example, conditioning with Listeria pathogen in memory T-cell study looks very smart and precise methodology. Another thing to try is antibody-based conditioning, if good specific surface markers of lung stem cells are identified.