As we age, the stem cells that generate our blood and immune cells, so-called hematopoietic stem cells (HSCs), lose their ability to regenerate and function. This decline can lead to anemia, weakened immune responses, and a higher risk of blood cancers like myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). While the transplantation of healthy donor stem cells can replace these faulty cells, current protocols in the clinic rely on toxic conditioning regimens that damage not just diseased cells, but healthy tissues too.
“Conventional transplantation requires patients to undergo chemotherapy or irradiation to eliminate malignant cells, suppress immune rejection, and make room for new stem cells in the bone marrow,” explains David Bryder, Professor of Molecular Hematology at Lund University. “But these treatments are highly toxic, especially for older individuals, who are also the ones most likely to benefit.”
Developing a way for safer stem cell transplantations
To solve this dilemma, the research team at Lund Stem Cell Center developed a non-genotoxic method for preparing an individual for stem cell transplantation – one that avoids harmful side effects, such as organ damage and severe systemic stress.
“Instead of using conventional chemotherapy, we deployed antibody-toxin conjugates, also known as immunotoxins, that selectively target and deplete the recipient’s own HSCs while sparing surrounding tissues," describes Anna Konturek-Ciesla, postdoctoral researcher and first author of the study.
"This was paired with a drug-based mobilization strategy that temporarily displaces stem cells from the bone marrow, creating space for incoming donor cells.”
Using in vitro methods previously validated by the team, the researchers expanded healthy HSCs in the lab before transplanting them into aged mice.
“This was an essential step given how rare these cells are in the body and how difficult it can be to obtain enough for transplantation,” adds Anna.
Replacing aged or malfunctioning blood stem cells
In doing so, they found that young donor cells successfully engrafted into the aging bone marrow and rebuilt the blood and immune systems with features typically seen in younger animals.
“In particular, the mice showed a strong resurgence in the production of naïve B and T lymphocytes, cells that play a key role in immune defense, which usually decline with age. These young cells didn’t just survive, they reshaped the entire immune landscape,” highlights David. “We were especially encouraged to see that the new cells maintained long-term function and diversity, even within an aged environment.”
In another stage of the study, the therapy was tested in a mouse model genetically predisposed to develop MDS. Here, the treatment reduced disease incidence and prevented the progression to AML, a severe and often fatal blood cancer.
“While these findings are currently limited to animal models, and there are many more steps to take before this can be applied in humans, they offer a proof-of-concept, that aged or malfunctioning stem cells can be safely replaced (without the toxicity of traditional conditioning) and that youthful blood production can be restored even in an older body,” summarizes Anna.
