Researchers from Pune’s National Centre for Cell Science (NCCS) have found that co-culturing aged haematopoietic stem cells with young mesenchymal stromal cells will rejuvenate the stem cells and improve their functionality. When done prior to transplantation, the rejuvenation will help improve the engrafting efficiency of stem cells. This novel method will expand the pool of donors for bone marrow transplantation.
Currently, haematopoietic stem cells taken from older donors for bone marrow transplantation have lower efficiency and capacity to engraft in recipients thus limiting their usefulness. But all this is set to change. Researchers from Pune’s National Centre for Cell Science (NCCS) have found novel ways to rejuvenate the haematopoietic stem cells taken from aged donors and restore their functionality prior to transplantation to improve their engrafting efficiency.
A team led by Dr. Vaijayanti Kale from the Stem Cell Lab at NCCS co-cultured aged haematopoietic stem cells and young mesenchymal stromal cells for 36 hours. The brief exposure was sufficient enough to rejuvenate the stem cells and improve their functionality. The improved functionality of stem cells increases their engraftment capacity when transplanted and improves the success rate of bone marrow transplantation. The results were published in the journal Stem Cells.
The researchers found that micro-vesicles from young mesenchymal stromal cells harbour significantly higher levels of autophagy-inducing mRNAs. The more the autophagy-inducing mRNAs the better is the ability of cells to destroy older cell components leaving room for the generation of new, younger cell components.
They found that transfer of micro-vesicles (containing significantly higher levels of autophagy-inducing mRNAs) from young mesenchymal stromal cells to aged haematopoietic stem cells during co-culturing leads to rejuvenation and improved functionality of stem cells.
“We found that young micro-vesicles reduced the proliferation of aged stem cells but improved their functionality in mice that received the stem cells,” she says. “The improved functionality came from autophagy-inducing mRNAs present in the micro-vesicles.”
“Tissue matching is not necessary for the use of stromal cells and thus can be taken from unmatched donors. Anyway, the stromal cells will not be transplanted. They are only used for co-culturing to provide the micro-vesicles. So bone marrow transplantation will not be compromised by using stromal cells for co-culturing,” says Dr. Kale.
As mesenchymal stromal cells age they tend to exhibit activated AKT signalling. This leads to the accumulation of two microRNAs in the exosomes; exosomes are another type of extra-cellular vesicles. When the exosomes with the two microRNAs get into stem cells it leads to the loss of autophagy-inducing mRNA in the stem cells. As a result, the stem cells become less functional.
“We found that treating the old stromal cells with chemical inhibitors blocks the AKT signalling and this makes the stromal cells ‘young-like’. The transfer of exosomes with inhibited AKT signalling from stromal cells into stem cells improves the functionality of the stem cells, just like co-culturing the aged stem cells with young stromal cells,” says Dr. Kale.
Older stem cells from a donor are co-cultured with young stromal cells taken from the placenta or cord blood or from the marrow of young donors to improve the functionality of the stem cells. Alternatively, by using chemical inhibitors to block AKT signalling, the stromal cells and stem cells can be taken from the same donor who is old and co-cultured prior to transplantation.
“Our work on mouse models shows that such short-duration, in vitro rejuvenation of aged haematopoietic stem cells will expand the pool of donors for bone marrow transplantation and other regenerative therapies,” she says.