Biology subjects

Grigoryan, A.

Publications and source records attributed to Grigoryan, A..

8 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

Plague-driven selection enriched familial Mediterranean fever mutations in Armenia

The discovery that positive selection due to resistance to malarial infection maintained the prevalence of sickle cell and other disease alleles was a landmark in evolution, genetics and epidemiology. Mutations in the MEFV gene causing familial Mediterranean fever with high frequency in Eastern Mediterranean populations give the only other strong candidates for a similar process. Here we estimate a pathogenic MEFV mutation burden in Armenians with a carrier rate of ~41%: a worldwide maximum. By combining these data with regional ancient MEFV genotypes spanning more than 60 centuries, we establish that the allele frequencies of three mutations M694V, M680I, and V726A underwent recent rapid increases, indicating positive selection with an onset consistent with the first Yersinia pestis plague pandemic, ~541 CE to 767 CE or even earlier in time, echoing functional data implying resistance to this infection as the selective agent. This extends to three the number of MEFV variants for which there is evidence for strong concurrent selection at this locus in the Eastern Mediterranean, making it unlikely that this geographic peak resulted from chance alone. Although bubonic plague was extremely widespread, the restricted geography of this selection points toward the Eastern Mediterranean as a longstanding enzootic centre with continuous recycling of outbreaks.

genomics↗

bioRxiv2026

Multi-omics profiling links epigenetic and lncRNA changes to early human endochondral ossification priming

Differentiation programs remain incompletely understood across stem cell types, including for human bone marrow mesenchymal stromal/stem (BM-MSCs) cells, a heterogenous population orchestrating bone formation and establishing a functional hematopoietic niche in the bone marrow. BM-MSCs form and repair bone through the evolutionarily conserved process of endochondral ossification (EO), initiated by deposition of a transient cartilage template subsequently remodeled into bone and bone marrow tissues. Despite their considerable potential for skeletal regeneration, the early molecular and cellular events underlying BM-MSCs commitment to EO remain elusive. To overcome donor dependent variability in chondrogenic potential that limits mechanistic studies, we here exploit OssiGel as a potent chondro-inductive extracellular matrix offering robust recapitulation of EO by BM-MSCs. Through multi-omics profiling of OssiGel-primed BM-MSCs, we identify rapid chromatin remodeling at chondrogenic loci as concomitant for lineage commitment. The emergence of a chondro-progenitor population is detected as early as 3 days in vivo and correlates with successful EO recapitulation. Mechanistically, we identify LINC02511 as novel enhancer-associated element involved in the onset of EO. We confirm presence of LINC02511 in human skeletal atlases, and its CRISPR-mediated silencing significantly impaired EO. By integrating human tissue engineering strategies with single cell multi-omics profiling, our study provides a framework for deciphering BM-MSCs fate decisions, highlighting the role of enhancer and non-coding elements as key determinants of early lineage specification. These findings advance our understanding of BM-MSCs biology and will prompt their translational exploitation in regenerative medicine.

cell biology↗

bioRxiv2026

Pyocyanin disrupts airway regeneration to favor chronic Pseudomonas aeruginosa infection

During chronic infections, host tissues undergo repeated cycles of injury and repair while being exposed to bacterial products. Although many virulence factors trigger immune responses, whether bacterial metabolites alter tissue architecture by disrupting regenerative programs remains largely unexplored. Here, using a primary-cell-derived human lung microtissue model, we show that the redox-active metabolite pyocyanin (PYO), produced by the opportunistic pathogen Pseudomonas aeruginosa, disrupts airway epithelial regeneration and reshapes tissue architecture, amplifying infection. PYO exposure impairs epithelial repair, leading to defects in mucociliary clearance and promoting bacterial growth. Single-cell transcriptomics and imaging reveal that PYO exposure during basal cell differentiation alters epithelial cell-type composition. Keratin-13-rich cells promote the emergence of squamous regions with defective ciliogenesis, resulting in functional defects. After characterizing how PYO remodels the epithelium, we tested how these changes impact bacterial fitness. Using transposon-insertion sequencing and live imaging of infections, we show that these regeneration defects improve the fitness of mutants that tend to form biofilms, a common feature of chronic infections. Together, our results reveal that PYO reshapes regenerative trajectories and tissue architecture in ways that subsequently alter infection outcomes, highlighting the role of secreted metabolites as potential modulators of tissue regeneration during chronic lung infections.

microbiology↗

bioRxiv2026

Engineering autologous ossicles for the personalized modeling of acute myeloid leukemia

Acute Myeloid Leukemia (AML) is the most lethal hematological malignancy in adults and is characterized by significant genetic and cytogenetic heterogeneity. This diversity drives substantial patient-to-patient variability in disease progression and therapeutic response. Increasing evidence indicates that bone marrow mesenchymal stem/stromal cells (MSCs) play a critical role in AML emergence, evolution and treatment resistance. However, progress in the field is challenged by the lack of experimental models supporting sustained AML survival while faithfully recapitulating the human bone marrow niche. Humanized ossicles (hOss) have recently emerged as ectopic human bone/bone marrow microenvironments composed of MSCs and hematopoietic elements, enabling improved AML engraftment in vivo. Nonetheless, those models typically exploit healthy MSCs largely because primary patient-derived cells exhibit diminished ossification potential. Here, we introduce OssiGel, a novel engineered human cartilage extracellular matrix produced by a mesenchymal cell line. We hypothesized that combining OssiGel with primary MSCs would enable the robust formation of hOss in healthy and malignant settings. We report that OssiGel supports fast and reproducible formation of hOss through endochondral ossification using MSCs isolated from both healthy and AML bone marrow samples. Within hOss, AML-MSCs were shown to persist long-term and to generate a human stromal microenvironment supporting the establishment of autologous AML hematopoietic cells, enabling the generation of autologous (autologOss). Single-cell RNA sequencing (scRNA-seq) revealed that autologOss recapitulate the majority of the AML blood populations observed in the corresponding patient bone marrow samples. Moreover, proof-of-concept sequencing of AML-MSCs from autologOss allowed predictive interrogation of interactions with leukemic populations and revealed the acquisition of an inflammatory-like phenotype, characteristic of AML. Taken together, our study establishes OssiGel as a novel platform for the robust engineering of autologous ossicles from AML patient samples. This provides a relevant tool to decipher patient-specific cellular interactions and drug responses, with potential translational value to broad hematological malignancies.

bioengineering↗

bioRxiv2025

Palaeoproteomic and genetic insights into millennial-scale dairy consumption in Armenia

Dairy products are a key component of the diet in Armenia today, yet the origins of milk consumption, its historical development, and genetic adaptations related to milk digestion in the region remain understudied. Here, we investigate the co-evolution of dairying practices and lactase persistence in Armenia through combined palaeoproteomic and genetic analyses spanning from prehistory to the present. Our palaeoproteomic results provide direct evidence for milk consumption in prehistoric Armenia and, in conjunction with existing regional data, indicate that dairying was an established component of the South Caucasus subsistence economy from at least the late fourth millennium BCE. We found evidence of milk consumption from multiple species across archaeological periods, with cattle milk representing the earliest confirmed evidence from the Chalcolithic period. Notably, milk proteins were predominantly recovered from high-altitude sites, suggesting that dairy consumption served as an adaptive strategy for harsh highland environmental conditions. In contrast to the widespread evidence for milk consumption, our genetic findings indicate that the lactase persistence-associated variants never reached high frequencies throughout Armenian prehistory. This pattern suggests that the relatively low frequency of lactase persistence may reflect a predominant cultural adaptation to the fermentation of dairy products, which reduces lactose content and enables dairy use even in genetically lactose-intolerant populations.

evolutionary biology↗

bioRxiv2021

Engineering of human mini-bones for the standardized modeling of healthy hematopoiesis, leukemia and solid tumor metastasis

The bone marrow microenvironment provides indispensable factors to sustain blood production throughout life. It is also a hotspot for the progression of hematologic disorders and the most frequent site of solid tumor metastasis. Pre-clinical research relies on xenograft mouse models, precluding the human-specific functional interactions of stem cells with their bone marrow microenvironment. Human mesenchymal cells can be exploited for the in vivo engineering of humanized ossicles (hOss). Those mini-bones provide a human niche conferring engraftment of human healthy and malignant blood samples, yet suffering from major reproducibility issue. Here, we report the standardized generation of hOss by developmental priming of a custom-designed human mesenchymal cell line. We demonstrate superior engraftment of cord blood hematopoietic cells and primary acute myeloid leukemia samples, but also validate our hOss as metastatic site for breast cancer cells. Finally, we report the first engraftment of neuroblastoma patient-derived xenograft cells in a humanized model, recapitulating clinically reported osteolytic lesions. Collectively, our hOss constitute a powerful standardized and malleable platform to model normal hematopoiesis, leukemia and solid tumor metastasis.

bioengineering↗

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↗