Biology subjects

Christman, K.

Publications and source records attributed to Christman, K..

5 recordsLinked to original sources

bioRxiv2021

The role of muscle stem cells and fibro-adipogenic progenitors in female pelvic floor muscle regeneration following birth injury

Pelvic floor muscle (PFM) injury during childbirth is a key risk factor for subsequent pelvic floor disorders that affect millions of women worldwide. Muscle stem cells (MuSCs) play a central role in the regeneration of injured skeletal muscles, where they activate, proliferate, and differentiate to assure myogenesis needed for muscle recovery. For robust regenerative function, MuSCs require the support of fibro-adipogenic progenitors (FAPs) and immune cells. To elucidate the role of MuSCs, FAPs, and immune infiltrate in female PFM regeneration, we used radiation to perturb the system and followed PFM recovery in a simulated birth injury (SBI) rat model. Non-irradiated and irradiated rats were euthanized at 3,7, 10, and 28 days after SBI; PFMs were harvested and prepared for immunohistochemistry. Cross sectional area (CSA) of all PFM myofibers 28 days after injury in irradiated animals was significantly lower relative to non-irradiated injured controls, indicating impairment of PFM recovery. Following SBI in non-irradiated animals, the number of MuSCs and FAPs expanded significantly at 7 and 3 days after injury, respectively; this expansion did not occur in irradiated animals at the same time points. CSA of embryonic myosin heavy chain (eMyHC, marker of newly regenerated myofibers) positive fibers was also significantly smaller following SBI in irradiated muscles compared to PFMs from non-irradiated injured controls at 7 days. Our results demonstrate that loss of function and decreased expansion of MuSCs and FAPs associated with irradiation results in impaired PFM recovery, signifying essential roles for MuSCs and FAPs in the regenerative process of female PFMs after birth injury. These findings can inform the identification of novel preventative and therapeutic targets and the development of new treatments for PFM dysfunction and associated pelvic floor disorders.

cell biology↗

bioRxiv2020

Preventing post-surgical cardiac adhesions with a catechol-functionalized oxime hydrogel

Post-surgical cardiac adhesions represent a significant problem during routine cardiothoracic procedures. This fibrous tissue can impair heart function and inhibit surgical access in reoperation procedures. Here, we propose a novel hydrogel barrier composed of oxime crosslinked poly(ethylene glycol) (PEG) with the inclusion of a catechol (Cat) group to improve retention on the heart for pericardial adhesion prevention. This three component system is comprised of aldehyde (Ald), aminooxy (AO), and Cat functionalized PEG mixed to form the final gel (Ald-AO-Cat). Ald-AO-Cat has favorable mechanical properties, degradation kinetics, and minimal swelling, as well as superior tissue retention compared to an initial Ald-AO gel formulation. We show that the material is cytocompatible, resists cell adhesion, and led to a reduction in the severity of adhesion in an in vivo rat model and a pilot porcine study. The Ald-AO-Cat hydrogel barrier may therefore serve as a promising solution for preventing post-surgical cardiac adhesions.

bioengineering↗

bioRxiv2020

Injectable Myocardial Matrix Hydrogel Mitigates Negative Left Ventricular Remodeling in a Chronic Myocardial Infarction Model

A first-in-man clinical study on a myocardial-derived decellularized extracellular matrix (ECM) hydrogel yielded evidence for potential efficacy in ischemic heart failure (HF) patients. However, little is understood about the mechanism of action in chronic myocardial infarction (MI). In this study we investigated efficacy and mechanism by which the myocardial matrix hydrogel can mitigate negative left ventricular (LV) remodeling in a chronic model of MI. Assessment of cardiac function via magnetic resonance imaging (MRI) demonstrated preservation of LV volumes and apical wall thickening. Differential gene expression analyses showed the matrix is able to prevent worsening HF in a small animal chronic MI model through modulation of the immune response, downregulation of pathways involved in HF progression and fibrosis, and upregulation of genes important for cardiac muscle contraction.

bioengineering↗

bioRxiv2020

Myocardial matrix material supports a proliferative microenvironment for cardiomyocytes

Novel therapeutics have sought to stimulate the endogenous repair mechanisms in the mammalian myocardium as the native regenerative potential of the adult cardiac tissue is limited. In particular, a myocardial matrix derived injectable hydrogel has shown efficacy and safety in various animal myocardial infarction (MI) including evidence of increased myocardium. In this study, investigation on the properties of this myocardial matrix material demonstrated its native capability as an effective reactive oxygen species (ROS) scavenger that can protect against oxidative stress and maintain cardiomyocyte proliferation in vitro. In vivo assessment of of myocardial matrix hydrogel treatment post-MI demonstrated increased thymidine analog uptake in cardiomyocytes compared to saline controls along with co-staining with cell cycle progression marker, phospho-histone H3. Overall, this study provides further evidence that properties of the myocardial matrix hydrogel promote an environment supportive of cardiomyocytes undergoing cell cycle progression.

bioengineering↗

bioRxiv2020

Mast Cells Contribute to the Immunomodulatory Effect of the Biomaterial Microenvironment in a Gender Specific Manner

Bioactive immunomodulatory biomaterials have shown promise for influencing the immune response to promote tissue repair and regeneration. Macrophages and T cells have been associated with this response; however, other immune cell types have been traditionally overlooked. In this study, we investigated the role of mast cells in the regulation of the immune response to decellularized biomaterial scaffolds using a subcutaneous implant model. In mast cell-deficient mice, there was dysregulation of the expected M1 to M2 macrophage transition typically induced by the biomaterial scaffold. Polarization progression deviated in a sex specific manner with an early transition to an M2 profile in female mice, while the male response was unable to properly transition past a pro-inflammatory M1 state. Both were reversed with adoptive mast cell transfer. Further investigation of the later stage immune response in male mice determined a greater sustained pro-inflammatory gene expression profile including the IL-1 cytokine family, IL-6, alarmins, and chemokines. These results highlight mast cells as another important cell type that influences the immune response to pro-regenerative biomaterials.

bioengineering↗