US researchers have reported a new approach to enhance the potency of haematopoietic stem cells (HSCs) in mice, which could eventually lead to improvements in bone marrow transplants.
Manipulation of metabolic activity around lysosomes can increase HSC potency by more than 90-fold, according to a recent report in the journal Cell Stem Cell.
The study was led by Dr Saghi Ghaffari, of the Black Family Stem Cell Institute and The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai Hospital, New York. The research team used an effective and specific lysosomal inhibitor in mice, which reduces lysosomal acidity and amino acid release in HSCs.
This resulted in the restoration of stem cells to a quiescent state. The researchers also found that only active, not quiescent, HSCs rely on glycolysis for their energy, and that the inhibition of glycolysis also enhances quiescence and potency of these HSCs.
“Hematopoietic stem cells lose their stem cell potential once they're cultured in a dish, which limits their ability to be easily propagated in the laboratory,” said Dr Ghaffari.
“In order for these stem cells to maintain optimal potency, they shouldn't be constantly dividing, putting them under metabolic stress that can alter their health and longevity. Instead, they should be in a dormant, or quiescent, state.
“But maintaining quiescence of blood stem cells outside of the body has been challenging. We discovered that lysosomes are key to the dormancy of these cells. We further learned that repressing lysosomal activity – rather than their stimulation – enhances stem cell quiescence and potency and may have therapeutic value.”
Dr Ghaffari said the team’s methodology is different from others who have tried to generate more HSCs in the lab, because theirs is based on quality rather than quantity.
“By restraining lysosomal activity we produce fewer blood-forming stem cells for bone marrow transplantation, but they work much better because we've preserved and enhanced their potency,” she said.
It is hoped the findings could eventually be used to generate blood stem cells from cultured pluripotent stem cells or to enhance the function of human blood stem cells for bone marrow transplantation.
Source: Liang R, Arif T, Kalmykova S, Kasianov A, Lin M, Menon V, Qiu J, Bernitz JM, Moore K, Lin F, Benson DL, Tzavaras N, Mahajan M, Papatsenko D, Ghaffari S (2020) “Restraining Lysosomal Activity Preserves Hematopoietic Stem Cell Quiescence and Potency”, Cell Stem Cell, doi: 10.1016/j.stem.2020.01.013
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