Biology subjects

Sakk, V.

Publications and source records attributed to Sakk, V..

5 recordsLinked to original sources

bioRxiv2026

An aged human bone marrow mesenchymal niche causes impaired function of human hematopoietic stem cells under regeneration-induced stress

Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) and are responsible for blood formation throughout life. With advancing age, HSCs show reduced functional capacity. While clear intrinsic cellular changes in human HSCs (hHSCs) occur during aging, it remains unclear how the human bone marrow (hBM) niche contributes to hHSC dysfunction. This research gap is largely due to a lack of suitable experimental models capable of replicating the organization and function of the aged hBM environment. This study demonstrates that aged hBM mesenchymal stromal cells (hBMSCs) act as important niche regulators of hHSC function by contributing to the myeloid-biased differentiation of young hHSCs. Furthermore, hBMSCs play a crucial role in protecting hHSCs during regeneration-induced stress while this protective function of hBMSCs is impaired with age.

cell biology↗

bioRxiv2026

The extent of myeloid skewing in blood is a biomarker of biological aging in mice and humans

Myeloid skewing is a central and therefore often cited hallmark of hematopoietic aging. Myeloid skewing refers to an elevated myeloid-to-lymphoid cell ratio in aged compared to young mice. Interestingly, whether the extent of myeloid skewing might be in itself a quantitative biological marker of aging has not been addressed yet, nor whether this parameter has also relevance for the extent of aging in humans. Aged mice with high level of myeloid skewing (>50% myeloid cells in blood) showed accelerated hematopoietic aging compared to mice with a low level of myeloid skewing (<30% of myeloid cells in blood), as well as an increased level of inflammatory cytokines and elevated levels of diseases. Hematopoietic stem cells (HSCs) from mice with high myeloid skewing showed an impaired repopulation capacity. Epigenetic clock analyses demonstrated that mice with a high level of myeloid skewing present with a biological age that is older than their chronological age. In humans, a high degree of myeloid skewing was associated with elevated levels of inflammatory markers, reduced mobility, a greater burden of comorbidities, and an increased mortality hazard ratio. The data support that, besides overall myeloid skewing being a central hallmark of aging in mice, the extent of the frequency of myeloid cells in blood might serve as a biological marker of aging and disease in both mice and humans. Key PointsThe extent of myeloid skewing in aged mice correlates to an increased hematological and epigenetic age and increased disease burden. The extent of myeloid skewing in older adults is associated with an increased hazard ratio of mortality and correlates with higher frailty and inflammatory markers.

cell biology↗

bioRxiv2021

A Cdc42-Borg4-Septin 7 axis regulates HSCs polarity and function

Aging of hematopoietic stem cells (HSCs) is caused by an elevated activity of the small RhoGTPase Cdc42 and an apolar distribution of proteins. Mechanisms by which Cdc42 activity controls polarity of HSCs are not known. Binder of RhoGTPases proteins (borgs) are known effector proteins of Cdc42 that are able to regulate the cytoskeletal septin network. Here we show that Cdc42 interacts with borg4, which in turn interacts with septin 7 to regulate the polar distribution of Cdc42, borg4 and septin 7 within HSCs. Genetic deletion of either borg4 or septin 7 in HSCs resulted in a reduced frequency of HSCs polar for Cdc42 or borg4 or septin 7 and a reduced engraftment potential and decreased lymphoid-primed multipotent progenitors (LMPPs) frequency in the bone marrow. In aggregation our data identify a Cdc42-borg4-septin 7 axis to be essential for maintenance of polarity within HSCs and for HSC function and provide rationale for further investigating the role of borgs and septins for the regulation of compartmentalization within stem cells. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/435817v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@168dd5org.highwire.dtl.DTLVardef@b9b4a3org.highwire.dtl.DTLVardef@26e05org.highwire.dtl.DTLVardef@1851fcf_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2020

A Wnt5a-Cdc42 axis controls aging and rejuvenation of hair-follicle stem cells

Normal hair growth occurs in cycles, comprising growth (anagen), cessation (catagen) and rest (telogen). Upon aging, the initiation of anagen is significantly delayed, which results in impaired hair regeneration. Hair regeneration is driven by hair follicle stem cells (HFSCs). We show here that aged HFSCs present with a decrease in canonical Wnt signaling and a shift towards non-canonical Wnt5a driven signaling which antagonizes canonical Wnt signaling. Elevated expression of Wnt5a in HFSCs upon aging results in elevated activity of the small RhoGTPase Cdc42 as well as a change in the spatial distribution of Cdc42 within HFSCs. Treatment of aged HFSC with a specific pharmacological inhibitor of Cdc42 activity termed CASIN to suppress the aging-associated elevated activity of Cdc42 restored canonical Wnt signaling in aged HFSCs. Treatment of aged mice in vivo with CASIN induced anagen onset and increased the percentage of anagen skin areas. Aging-associated functional deficits of HFSCs are at least in part intrinsic to HFSCs and can be restored by rational pharmacological approaches.

cell biology↗

bioRxiv2018

Epigenetic Age-Predictor for Mice based on Three CpG Sites

Epigenetic clocks for mice were generated based on deep-sequencing analysis of the methylome. In this study we demonstrate that site-specific analysis of DNA methylation levels by pyrosequencing at only three CG dinucleotides (CpGs) in the genes Prima1, Hsf4, and Kcns1 facilitates precise estimation of chronological age in murine blood samples, too. DBA/2J mice revealed accelerated epigenetic aging as compared to C57BL6 mice, which is in line with their shorter life-expectancy. The three-CpG-predictor provides a simple and cost-effective biomarker to determine biological age in large intervention studies with mice.

genomics↗