Targeting RhoA activity rejuvenates aged hematopoietic stem cells
Posted on: 24 September 2025 , updated on: 30 September 2025
Preprint posted on 23 April 2025
Categories: cell biology
FocalPlane features… preLights webinar recording: https://focalplane.biologists.com/2025/09/25/focalplane-features-prelights-recording/
What I like most about the preprint
What I find particularly interesting about the findings presented in this study is how it associates nuclear mechanosignalling with the aging of hematopoietic stem cells (HSCs). I specifically appreciated the clarity of the mechanism described: the authors beautifully established links between Klf4 activation and actin polymerization, nuclear stiffness, and reprogramming-like signatures, proposing a coherent explanation for how cytoskeletal changes can reshape nuclear function and chromatin state. This offers a new viewpoint on stem cell aging, moving beyond descriptive correlations.
Background and hypothesis.
Many diseases are linked to aging. With age, hematopoietic stem cells (HSCs) lose their regenerative and lymphoid-supporting capacity. Aging is also coupled to biomechanical changes in cells, particularly nuclear envelope (NE) tension. Such alterations impair nuclear integrity and mechanotransduction, thus affecting stem cell function.
The small GTPase RhoA, a key mechanotransducer, is activated in response to aberrations in cell mechanics. In HSCs, RhoA is essential for cytokinesis, maintaining blood cell production, and its depletion results in hematopoietic failure. The authors of this study demonstrate upregulation of RhoA activity in response to increased NE tension in aged HSCs. Moreover, they show that this process can be targeted to restore nuclear architecture and stem cell function in aged HSCs.
Key findings explained using an analogy.
Nuclear envelope as an overstretched balloon:
Imagine the nucleus of a stem cell as a balloon. The balloon (= nucleus) is firm and resistant in young cells. However, the balloon is stretched too much (increased NE tension) in aging cells, resulting in a loss of its shape, triggering disorganization of the content inside (= chromatin). When the stretched balloon is brought back to its original state (through RhoA inhibition), the balloon bounces back to its original shape, and the chromatin re-organized (leading to healthy gene expression and function, Figure 1).
by Ri treatment in aged HSCs.
Key findings in a list.
- Aging phenotypes in HSCs are driven by RhoA overactivation: Aging HSCs displayed elevated nuclear envelope (NE) tension and decreased H3K9 methylation (heterochromatin histone marker in aged HSCs), resulting in RhoA overactivation. This causes nuclear stretching, chromatin decompaction, leading to diminished regenerative competence and altered blood cell production (more myeloid, fewer lymphoid cells).
- Pharmacological inhibition of RhoA rejuvenates aged HSCs: Utilizing a specific RhoA inhibitor, Ri, the authors demonstrated restoration of young stem cell features in aged HSCs— for instance, chromatin compaction, lower NE mechanics, reduced inflammatory gene expression, and enhanced regenerative potential in transplantation assays.
- Klf4 activation is crucial in reprogramming aged HSCs: Further, RhoA inhibition in aged HSCs reactivates Klf4, a transcription factor associated with stemness and actin polymerization. This led to a stable nuclear structure and stimulated partial reprogramming toward becoming a functional young HSC again.
The big picture.
Findings in this article are clinically significant as they identify a new pharmacologically targetable mechano-signaling approach to reverse a key aspect of aging in stem cells. Simply put, this study describes the mechanics behind hematopoietic stem cell (HSCs) aging. It links bone marrow stiffening with age and physical stress on HSCs. This approach opens up new possibilities when designing therapies for age-related blood disorders and compromised immunity, potentially boosting the health and lifespan of older adults.
Open Questions.
Q 1: Are there any mechanosensitive molecules that potentially translate alteration in cell mechanics to RhoA in aged HSCs?
Q 2: Is the effect of Rhosin on aged stem cells long-lasting or short lived? What happens to the rejuvenated HSCs if the inhibitor is withdrawn?
Q 3: Do you foresee a similar mechanotransduction mechanism in aging of other somatic stem cells, for example those in muscle tissue?
doi: https://doi.org/10.1242/prelights.41451
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