Summary: YTHDF2 is a key protein that helps preserve healthy blood formation by regulating inflammatory responses in blood-forming stem cells.
Source: University of Edinburgh
New research reveals a protein with a vital role in protecting the blood system’s stem cells from premature decline, ensuring their ability to generate blood and immune cells throughout life.
Researchers report that the protein YTHDF2 shields hematopoietic stem cells (HSCs) from inflammatory damage during immune responses, allowing these long-lived stem cells to maintain proper function over time.
Preventing Stem Cell Burnout
Hematopoietic stem cells must rapidly scale up production of specialised immune cells when the body encounters infection, yet scientists have long asked how HSCs avoid becoming exhausted by repeated inflammatory challenges. Previous studies have linked YTHDF2 to healthy blood development, and the new work probes how this protein protects stem cells under inflammatory stress.
A collaborative team led by the University of Edinburgh and Queen Mary University of London examined mice genetically engineered to lack YTHDF2 to determine the protein’s role in the maintenance and resilience of blood stem cells. To model a viral-like immune challenge, young YTHDF2-deficient mice were treated with a compound that triggers an inflammatory response, allowing the researchers to observe how the absence of YTHDF2 altered HSC behaviour during and after inflammation.
Regulating Inflammation to Protect Stem Cells
The investigators found that HSCs from YTHDF2-deficient mice showed persistent activation of inflammatory pathways. This chronic inflammation reduced the long-term capacity of those stem cells to regenerate the full range of blood cell types. Normally, when infections occur, HSCs temporarily increase production of specialised immune cells. That emergency response must be tightly controlled so the stem cells are not driven into a lasting dysfunctional state.
The study demonstrates that YTHDF2 acts as a regulator of gene activity linked to inflammation, suppressing proinflammatory signals and thereby preserving HSC integrity. Without YTHDF2, inflammation-related transcripts accumulate and inflammatory pathways remain active, which undermines the stem cells’ regenerative potential over time.
Signs of Premature Ageing in Blood
Loss of YTHDF2 in young mice produced changes in blood cell composition that resembled the patterns seen in much older animals. During normal ageing, HSCs gradually lose potency and their ability to generate balanced blood lineages, contributing to reduced immune resilience in older adults. The YTHDF2-deficient mice developed a progressive bias toward myeloid cell production and a decline in lymphoid potential, consistent with accelerated ageing of the hematopoietic system.
The findings indicate that YTHDF2 is required to restrain inflammatory programmes that, when chronically active, lead to stem cell dysfunction and altered blood production. The research team notes that further work is needed to determine whether adjusting YTHDF2 activity during ageing could help preserve stem cell function and improve immune responses in older individuals.
This study was conducted in collaboration with Harvard Medical School, Georg-Speyer-Haus and Goethe University, and the University of Oxford, and the results were published in the Journal of Experimental Medicine.
Funding: Supported by Cancer Research UK, Barts Charity and Wellcome.
About this genetics and aging research news
Source: University of Edinburgh
Contact: Press Office – University of Edinburgh
Image: Image credited to Andrejs Ivanovs
Original Research: Open access. “The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function” by O’Carroll et al., Journal of Experimental Medicine. DOI: 10.1084/jem.20200829
Abstract (rephrased)
The mRNA N6-methyladenosine (m6A) reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function
Chemical modification of mRNA known as N6-methyladenosine (m6A) plays a crucial role in both normal and malignant blood formation. YTHDF2 is a reader protein that binds m6A-modified transcripts and promotes their degradation. Previous work showed that inactivation of YTHDF2 expands HSC numbers and interferes with acute myeloid leukemia progression. The present study examines how deleting YTHDF2 affects long-term HSC maintenance and multilineage hematopoiesis. Ythdf2-deficient HSCs from young mice fail under serial transplantation, accumulate multiple inflammation-related m6A-modified transcripts, and chronically activate proinflammatory pathways. Consistent with the harmful effects of sustained inflammation in HSCs, loss of Ythdf2 in hematopoietic cells causes progressive myeloid skewing, reduced lymphoid potential, HSC expansion, and eventual failure of aged Ythdf2-deficient HSCs to reconstitute diverse blood lineages. Experimentally induced inflammation elevates YTHDF2 expression, and YTHDF2 is required to protect HSCs from inflammatory insult. These results position YTHDF2 as a repressor of inflammatory pathways in HSCs and underline the importance of m6A regulation for long-term stem cell maintenance.