Biology subjects

Novak, S.

Publications and source records attributed to Novak, S..

3 recordsLinked to original sources

bioRxiv2024

Effects of Aging on the Immune and Periosteal Response to Fracture in Mice

Aging predisposes individuals to reduced bone mass and fragility fractures, which are costly and linked to high mortality. Understanding how aging affects fracture healing is essential for developing therapies to enhance bone regeneration in older adults. During the inflammatory phase of fracture healing, immune cells are recruited to the injury site as periosteal skeletal stem/progenitor cells (pSSPCs) rapidly proliferate and differentiate into osteochondral lineages, allowing for fibrocartilaginous callus formation and complete bone healing. Irrespective of age, how periosteal mesenchymal and immune cells interact during early fracture healing is incompletely understood, limiting our ability to potentially modulate these processes. To address this, we directly analyzed, in parallel, at a single-cell level, isolated murine CD45(+) and CD45(-) periosteal cells dissected from intact and fractured bones, collected three days after injury. Through comprehensive analysis, corroborated by bulk RNA-sequencing, flow cytometry, and histology, we found aging decreases pSSPCs proliferative, marked by a reduced expression of genes required for callus formation and an increased senescence signature. We found that the chemokine Cxcl9 was highly upregulated in aged intact Prrx1+ pSSPCs, predicted to interact with other pSSPCs directly, and associated with increased recruitment of CD8+ T cells at the fracture site three days after injury. Cell-to-cell communication analysis provided insight into the complexity of interactions among the many cell types regulating fracture healing and the impact of aging on these processes. Together, these results provide insight into age-induced alterations in fracture healing, informing the development of improved therapeutic approaches for fragility fractures.

cell biology↗

bioRxiv2020

Heterogeneity of murine periosteum osteochondroprogenitors involved in fracture healing

The periosteum is the major source of cells involved in fracture healing. We sought to characterize progenitor cells and their contribution to bone fracture healing. The periosteum is highly enriched for progenitor cells, including Sca1+ cells, CFU-F and label-retaining cells compared to the endosteum and bone marrow. Using lineage tracing, we demonstrate that SMA identifies long-term, slow-cycling, self-renewing osteochondroprogenitors in the adult periosteum that are functionally important for bone formation during fracture healing. In addition, Col2.3CreER-labeled osteoblast cells contribute around 10% of osteoblasts, but no chondrocytes in fracture calluses. Most periosteal osteochondroprogenitors following fracture, can be targeted by SMACreER. Previously identified skeletal stem cell populations were common in periosteum, but contained high proportions of mature osteoblasts. We have demonstrated that the periosteum is highly enriched for skeletal progenitor cells and there is heterogeneity in the populations of cells that contribute to mature lineages during periosteal fracture healing.

developmental biology↗

bioRxiv2017

Cardiac enriched BAF chromatin remodeling complex subunit Baf60c regulates gene expression programs essential for heart development and function

How gene networks controlling organ-specific properties are modulated by chromatin remodeling complexes is not well understood. Baf60c (Smarcd3) encodes a cardiac-enriched subunit of the SWI/SNF-like BAF chromatin complex. Its role throughout heart development is not fully understood. We show that constitutive loss of Baf60c leads to embryonic cardiac hypoplasia and pronounced cardiac dysfunction. Conditional deletion of Baf60c in cardiomyocytes results in postnatal dilated cardiomyopathy with impaired contractile function. Baf60c regulates a gene expression program that includes genes encoding contractile proteins, modulators of sarcomere function, and cardiac metabolic genes. Many of the genes deregulated in Baf60c null embryos are targets of the MEF2/SRF co-factor Myocardin (MYOCD). In a yeast two-hybrid screen we identify MYOCD as a BAF60c interacting factor; we show that BAF60c and MYOCD directly and functionally interact. We conclude that Baf60c is essential for coordinating a program of gene expression that regulates the fundamental functional properties of cardiomyocytes.

developmental biology↗