Publications by authors named "Dakota L Jones"

16 Publications

  • Page 1 of 1

ZNF416 is a pivotal transcriptional regulator of fibroblast mechanoactivation.

J Cell Biol 2021 May;220(5)

Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN.

Matrix stiffness is a central regulator of fibroblast function. However, the transcriptional mechanisms linking matrix stiffness to changes in fibroblast phenotype are incompletely understood. Here, we evaluated the effect of matrix stiffness on genome-wide chromatin accessibility in freshly isolated lung fibroblasts using ATAC-seq. We found higher matrix stiffness profoundly increased global chromatin accessibility relative to lower matrix stiffness, and these alterations were in close genomic proximity to known profibrotic gene programs. Motif analysis of these regulated genomic loci identified ZNF416 as a putative mediator of fibroblast stiffness responses. Genome occupancy analysis using ChIP-seq confirmed that ZNF416 occupies a broad range of genes implicated in fibroblast activation and tissue fibrosis, with relatively little overlap in genomic occupancy with other mechanoresponsive and profibrotic transcriptional regulators. Using loss- and gain-of-function studies, we demonstrated that ZNF416 plays a critical role in fibroblast proliferation, extracellular matrix synthesis, and contractile function. Together, these observations identify ZNF416 as novel mechano-activated transcriptional regulator of fibroblast biology.
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http://dx.doi.org/10.1083/jcb.202007152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918622PMC
May 2021

Vascular dysfunction in aged mice contributes to persistent lung fibrosis.

Aging Cell 2020 08 21;19(8):e13196. Epub 2020 Jul 21.

Department of Medicine, Boston University School of Medicine, Boston, MA, USA.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease thought to result from impaired lung repair following injury and is strongly associated with aging. While vascular alterations have been associated with IPF previously, the contribution of lung vasculature during injury resolution and fibrosis is not well understood. To compare the role of endothelial cells (ECs) in resolving and non-resolving models of lung fibrosis, we applied bleomycin intratracheally to young and aged mice. We found that injury in aged mice elicited capillary rarefaction, while injury in young mice resulted in increased capillary density. ECs from the lungs of injured aged mice relative to young mice demonstrated elevated pro-fibrotic and reduced vascular homeostasis gene expression. Among the latter, Nos3 (encoding the enzyme endothelial nitric oxide synthase, eNOS) was transiently upregulated in lung ECs from young but not aged mice following injury. Young mice deficient in eNOS recapitulated the non-resolving lung fibrosis observed in aged animals following injury, suggesting that eNOS directly participates in lung fibrosis resolution. Activation of the NO receptor soluble guanylate cyclase in human lung fibroblasts reduced TGFβ-induced pro-fibrotic gene and protein expression. Additionally, loss of eNOS in human lung ECs reduced the suppression of TGFβ-induced lung fibroblast activation in 2D and 3D co-cultures. Altogether, our results demonstrate that persistent lung fibrosis in aged mice is accompanied by capillary rarefaction, loss of EC identity, and impaired eNOS expression. Targeting vascular function may thus be critical to promote lung repair and fibrosis resolution in aging and IPF.
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http://dx.doi.org/10.1111/acel.13196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431829PMC
August 2020

TBK1 regulates YAP/TAZ and fibrogenic fibroblast activation.

Am J Physiol Lung Cell Mol Physiol 2020 05 11;318(5):L852-L863. Epub 2020 Mar 11.

Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.

Idiopathic pulmonary fibrosis (IPF) results in scarring of the lungs by excessive extracellular matrix (ECM) production. Resident fibroblasts are the major cell type involved in ECM deposition. The biochemical pathways that facilitate pathological fibroblast activation leading to aberrant ECM deposition are not fully understood. Tank binding protein kinase-1 (TBK1) is a kinase that regulates multiple signaling pathways and was recently identified as a candidate regulator of fibroblast activation in a large-scale small-interfering RNA (siRNA) screen. To determine the effect of TBK1 on fibroblast activation, TBK1 was inhibited pharmacologically (MRT-68601) and genetically (siRNA) in normal and IPF human lung fibroblasts. Reducing the activity or expression of TBK1 led to reduction in α-smooth muscle actin stress fiber levels by 40-60% and deposition of ECM components collagen I and fibronectin by 50% in TGF-β-stimulated normal and IPF fibroblasts. YAP and TAZ are homologous mechanoregulatory profibrotic transcription cofactors known to regulate fibroblast activation. TBK1 knockdown or inhibition decreased the total and nuclear protein levels of YAP/TAZ. Additionally, low cell-cell contact and increased ECM substrate stiffness augmented the phosphorylation and activation of TBK1, consistent with cues that regulate YAP/TAZ. The action of TBK1 toward YAP/TAZ activation was independent of LATS1/2 and canonical downstream TBK1 signaling mediator IRF3 but dependent on proteasomal machinery of the cell. This study identifies TBK1 as a fibrogenic activator of human pulmonary fibroblasts, suggesting TBK1 may be a novel therapeutic target in pulmonary fibrosis.
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http://dx.doi.org/10.1152/ajplung.00324.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272740PMC
May 2020

A multi-chamber tissue culture device for load-dependent parallel evaluation of tendon explants.

BMC Musculoskelet Disord 2019 Nov 18;20(1):549. Epub 2019 Nov 18.

Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

Background: Injuries in the musculoskeletal system, such as tendon and ligament ruptures, are challenging to manage and often require surgical reconstructions with limited long-term success. Thus, characterizations of these tissues are urgently needed to better understand cellular mechanisms that regulate tissue homeostasis and healing. Explant culturing systems allow for ex vivo analysis of tissues in an environment that mimics the native microenvironment in vivo.

Methods: Collaborative efforts within our institution facilitated the establishment of a novel explant culturing system. Tissue specimens cultured in single wells, with individual applied loading and/or biological environment, allowed characterization of tissue cultured under a variety of biological loading conditions. Quantitative PCR analysis for selected gene markers was our primary outcome.

Results: Data were stratified for analysis by either culture environment or loading condition. Our gene expression results show that specimens clustered by culture condition may differ in molecular markers related to ECM production (e.g., Col1a1, Adamts4) and/or organization (e.g., Tnc, Dnc). In contrast, loading condition did significantly alter the median gene expression levels of tissues in comparison to unloaded control samples, although gene expression values related to ECM degradation (e.g., Mmp1, Mmp10) were altered in tendons cultured under tension in the device.

Conclusion: Our study demonstrates promising utility of a novel explant culturing system for further characterization of musculoskeletal tissues such as native tendons and ligaments, as well as pathologic fibrotic tissues resulting from arthrofibrosis or Dupuytren's disease.
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http://dx.doi.org/10.1186/s12891-019-2896-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862789PMC
November 2019

Selective YAP/TAZ inhibition in fibroblasts via dopamine receptor D1 agonism reverses fibrosis.

Sci Transl Med 2019 10;11(516)

Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.

Tissue fibrosis is characterized by uncontrolled deposition and diminished clearance of fibrous connective tissue proteins, ultimately leading to organ scarring. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) have recently emerged as pivotal drivers of mesenchymal cell activation in human fibrosis. Therapeutic strategies inhibiting YAP and TAZ have been hindered by the critical role that these proteins play in regeneration and homeostasis in different cell types. Here, we find that the Gα-coupled dopamine receptor D1 (DRD1) is preferentially expressed in lung and liver mesenchymal cells relative to other resident cells of these organs. Agonism of DRD1 selectively inhibits YAP/TAZ function in mesenchymal cells and shifts their phenotype from profibrotic to fibrosis resolving, reversing in vitro extracellular matrix stiffening and in vivo tissue fibrosis in mouse models. Aromatic l-amino acid decarboxylase [DOPA decarboxylase (DDC)], the enzyme responsible for the final step in biosynthesis of dopamine, is decreased in the lungs of subjects with idiopathic pulmonary fibrosis, and its expression inversely correlates with disease severity, consistent with an endogenous protective role for dopamine signaling that is lost in pulmonary fibrosis. Together, these findings establish a pharmacologically tractable and cell-selective approach to targeting YAP/TAZ via DRD1 that reverses fibrosis in mice.
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http://dx.doi.org/10.1126/scitranslmed.aau6296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066514PMC
October 2019

TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression.

J Cell Sci 2019 10 18;132(20). Epub 2019 Oct 18.

Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA

Tissue fibrosis is a chronic disease driven by persistent fibroblast activation that has recently been linked to epigenetic modifications. Here, we screened a small library of epigenetic small-molecule modulators to identify compounds capable of inhibiting or reversing TGFβ-mediated fibroblast activation. We identified pracinostat, an HDAC inhibitor, as a potent attenuator of lung fibroblast activation and confirmed its efficacy in patient-derived fibroblasts isolated from fibrotic lung tissue. Mechanistically, we found that HDAC-dependent transcriptional repression was an early and essential event in TGFβ-mediated fibroblast activation. Treatment of lung fibroblasts with pracinostat broadly attenuated TGFβ-mediated epigenetic repression and promoted fibroblast quiescence. We confirmed a specific role for HDAC-dependent histone deacetylation in the promoter region of the anti-fibrotic gene () in response to TGFβ stimulation. Finally, we identified HDAC7 as a key factor whose siRNA-mediated knockdown attenuates fibroblast activation without altering global histone acetylation. Together, these results provide novel mechanistic insight into the essential role HDACs play in TGFβ-mediated fibroblast activation via targeted gene repression.
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http://dx.doi.org/10.1242/jcs.233486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826010PMC
October 2019

PGC1α repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state.

Thorax 2019 08 10;74(8):749-760. Epub 2019 Jun 10.

Physiology & Biomedical Engineering, Mayo Clinic Minnesota, Rochester, Minnesota, USA

Idiopathic pulmonary fibrosis (IPF) is a fatal ageing-related disease linked to mitochondrial dysfunction. The present study aimed to determine whether peroxisome proliferator activated receptor gamma co-activator 1-alpha (, encoding PGC1α), a master regulator of mitochondrial biogenesis, is diminished in IPF and controls pathologic fibroblast activation. Primary human IPF, control lung fibroblasts and fibroblasts sorted from bleomycin-injured mice were used to evaluate the expression and function of PGC1α. In vitro PGC1α manipulation was performed by small interfering RNA knockdown or overexpression. Fibroblast activation was assessed by quantitative PCR, Western blotting, matrix deposition, secreted cytokine array, immunofluorescence and traction force microscopy. Mitochondrial function was assessed by Seahorse analyzer and mitochondria mass and number by flow cytometry, mitochondrial DNA quantification and transmission electron microscopy (TEM). We found that PGC1α levels are stably repressed in IPF fibroblasts. After bleomycin injury in young mice, PGC1α expression drops transiently but then increases prior to fibrosis resolution. In contrast, PGC1α expression fails to recover in aged mice with persistent fibrosis. PGC1α knockdown alone in normal human lung fibroblasts reduces mitochondrial mass and function while enhancing contractile and matrix synthetic fibroblast activation, senescence-related gene expression and soluble profibrotic and prosenescence signalling. Re-expression of PGC1α in IPF fibroblasts ameliorates all of these pathological cellular functions. Pharmacological treatment of IPF fibroblasts with rosiglitazone, but not thyroid hormone, elevated PGC1α expression and attenuated fibroblast activation. The sustained repression of PGC1α and beneficial effects of its rescue in IPF fibroblasts identifies PGC1α as an important regulator of the fibroblast's pathological state in IPF.
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http://dx.doi.org/10.1136/thoraxjnl-2019-213064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703129PMC
August 2019

CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation during lung fibrosis.

JCI Insight 2019 05 16;5. Epub 2019 May 16.

Department of Physiology and Biomedical Engineering.

Pulmonary fibrosis is a devastating disease characterized by accumulation of activated fibroblasts and scarring in the lung. While fibroblast activation in physiological wound repair reverses spontaneously, fibroblast activation in fibrosis is aberrantly sustained. Here we identified histone 3 lysine 9 methylation (H3K9me) as a critical epigenetic modification that sustains fibroblast activation by repressing the transcription of genes essential to returning lung fibroblasts to an inactive state. We show that the histone methyltransferase G9a (EHMT2) and chromobox homolog 5 (CBX5, also known as HP1α), which deposit H3K9me marks and assemble an associated repressor complex respectively, are essential to initiation and maintenance of fibroblast activation specifically through epigenetic repression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha gene (PPARGC1A, encoding PGC1α). Both TGFβ and increased matrix stiffness potently inhibit PGC1α expression in lung fibroblasts through engagement of the CBX5/G9a pathway. Inhibition of CBX5/G9a pathway in fibroblasts elevates PGC1α, attenuates TGFβ- and matrix stiffness-promoted H3K9 methylation, and reduces collagen accumulation in the lungs following bleomycin injury. Our results demonstrate that epigenetic silencing mediated by H3K9 methylation is essential for both biochemical and biomechanical fibroblast activation, and that targeting this epigenetic pathway may provide therapeutic benefit by returning lung fibroblasts to quiescence.
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http://dx.doi.org/10.1172/jci.insight.127111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629126PMC
May 2019

Nascent Lung Organoids Reveal Epithelium- and Bone Morphogenetic Protein-mediated Suppression of Fibroblast Activation.

Am J Respir Cell Mol Biol 2019 11;61(5):607-619

Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.

Reciprocal epithelial-mesenchymal interactions are pivotal in lung development, homeostasis, injury, and repair. Organoids have been used to investigate such interactions, but with a major focus on epithelial responses to mesenchyme and less attention to epithelial effects on mesenchyme. In the present study, we used nascent organoids composed of human and mouse lung epithelial and mesenchymal cells to demonstrate that healthy lung epithelium dramatically represses transcriptional, contractile, and matrix synthetic functions of lung fibroblasts. Repression of fibroblast activation requires signaling via the bone morphogenetic protein (BMP) pathway. BMP signaling is diminished after epithelial injury and , and exogenous BMP4 restores fibroblast repression in injured organoids. In contrast, inhibition of BMP signaling in healthy organoids is sufficient to derepress fibroblast matrix synthetic function. Our results reveal potent repression of fibroblast activation by healthy lung epithelium and a novel mechanism by which epithelial loss or injury is intrinsically coupled to mesenchymal activation via loss of repressive BMP signaling.
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http://dx.doi.org/10.1165/rcmb.2018-0390OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827068PMC
November 2019

Survivin IPF: Targeting Cellular Metabolism to Promote Apoptosis in IPF Fibroblasts.

Am J Respir Cell Mol Biol 2019 01;60(1):5-6

1 Department of Physiology and Biomedical Engineering Mayo Clinic Rochester, Minnesota.

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http://dx.doi.org/10.1165/rcmb.2018-0270EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348721PMC
January 2019

Safety Studies for Use of Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells in a Rabbit Model for Osteoarthritis to Support a Phase I Clinical Trial.

Stem Cells Transl Med 2017 03 26;6(3):910-922. Epub 2016 Oct 26.

Department of Orthopedic Surgery, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Adipose-derived mesenchymal stem cells (AMSCs) offer potential as a therapeutic option for clinical applications in musculoskeletal regenerative medicine because of their immunomodulatory functions and capacity for trilineage differentiation. In preparation for a phase I clinical trial using AMSCs to treat patients with osteoarthritis, we carried out preclinical studies to assess the safety of human AMSCs within the intra-articular joint space. Culture-expanded human AMSCs grown in human platelet-lysate were delivered via intra-articular injections into normal healthy rabbit knees and knees at risk for the development of osteoarthritis after bilateral medial anterior hemimeniscectomy. Treatment outcomes and safety were evaluated by assessing the general health, function, and behavior of the animals. Joint tissues were analyzed by x-ray, magnetic resonance imaging, and histopathology. Intra-articular AMSC therapy was well tolerated in this study. We did not observe adverse systemic reactions, nor did we find evidence of damage to intra-articular joint tissues. Thus, the data generated in this study show a favorable safety profile for AMSCs within the joint space in support of a phase I clinical trial evaluating the clinical utility of AMSCs to treat osteoarthritis. Stem Cells Translational Medicine 2017;6:910-922.
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http://dx.doi.org/10.5966/sctm.2016-0097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442773PMC
March 2017

RNA-seq analysis of clinical-grade osteochondral allografts reveals activation of early response genes.

J Orthop Res 2016 11 3;34(11):1950-1959. Epub 2016 Mar 3.

Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.

Preservation of osteochondral allografts used for transplantation is critical to ensure favorable outcomes for patients after surgical treatment of cartilage defects. To study the biological effects of protocols currently used for cartilage storage, we investigated differences in gene expression between stored allograft cartilage and fresh cartilage from living donors using high throughput molecular screening strategies. We applied next generation RNA sequencing (RNA-seq) and real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR) to assess genome-wide differences in mRNA expression between stored allograft cartilage and fresh cartilage tissue from living donors. Gene ontology analysis was used to characterize biological pathways associated with differentially expressed genes. Our studies establish reduced levels of mRNAs encoding cartilage related extracellular matrix (ECM) proteins (i.e., COL1A1, COL2A1, COL10A1, ACAN, DCN, HAPLN1, TNC, and COMP) in stored cartilage. These changes occur concomitantly with increased expression of "early response genes" that encode transcription factors mediating stress/cytoprotective responses (i.e., EGR1, EGR2, EGR3, MYC, FOS, FOSB, FOSL1, FOSL2, JUN, JUNB, and JUND). The elevated expression of "early response genes" and reduced levels of ECM-related mRNAs in stored cartilage allografts suggests that tissue viability may be maintained by a cytoprotective program that reduces cell metabolic activity. These findings have potential implications for future studies focused on quality assessment and clinical optimization of osteochondral allografts used for cartilage transplantation. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1950-1959, 2016.
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http://dx.doi.org/10.1002/jor.23209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993686PMC
November 2016

Human Adipose-Derived Mesenchymal Stromal/Stem Cells Remain Viable and Metabolically Active Following Needle Passage.

PM R 2016 09 28;8(9):844-54. Epub 2016 Jan 28.

Department of Physical Medicine & Rehabilitation, W14, Mayo Building, Mayo Clinic, 200 1st St, SW, Rochester, MN 55905; Department of Radiology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN; Department of Anatomy, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN(‡‡). Electronic address:

Objective: To assess the biological effects of passage through clinically relevant needles on the viability and metabolic activity of culture-expanded, human adipose tissue-derived mesenchymal stromal/stem cells (AMSCs).

Design: Prospective observational pilot study.

Setting: Academic medical center.

Participants: Patient-derived clinical-grade culture expanded AMSCs.

Interventions: AMSCs were passed through syringes without a needle attached (control), with an 18-gauge (25.4-mm) needle attached and with a 30-gauge (19-mm) needle attached at a constant injection flow rate and constant cell concentrations. Each injection condition was completed in triplicate.

Main Outcome Measures: Cell number and viability, proliferative capacity, metabolic activity, and acute gene expression as measured by cell counts, mitochondrial activity, and quantitative real time reverse-transcription polymerase chain reaction on day 0 (immediately), day 1, and day 4 after injection.

Results: AMSC viability was not significantly affected by injection, and cells proliferated normally regardless of study group. Postinjection, AMSCs robustly expressed both proliferation markers and extracellular matrix proteins. Stress-response mRNAs were markedly but transiently increased independently of needle size within the first day in culture postinjection.

Conclusions: Human, culture-expanded AMSCs maintain their viability, proliferative capacity, and metabolic function following passage through needles as small as 30-gauge at constant flow rates of 4 mL/min, despite an early, nonspecific stress/cytoprotective response. These initial findings suggest that culture-expanded AMSCs should tolerate the injection process during most cell-based therapeutic interventions.
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http://dx.doi.org/10.1016/j.pmrj.2016.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724701PMC
September 2016

Osteogenic potential of human adipose-tissue-derived mesenchymal stromal cells cultured on 3D-printed porous structured titanium.

Gene 2016 May 13;581(2):95-106. Epub 2016 Jan 13.

Department of Orthopedic Surgery, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA; Department of Biomedical Engineering and Physiology, Mayo Graduate School, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. Electronic address:

Integration of porous metal prosthetics, which restore form and function of irreversibly damaged joints, into remaining healthy bone is critical for implant success. We investigated the biological properties of adipose-tissue-derived mesenchymal stromal/stem cells (AMSCs) and addressed their potential to alter the in vitro microenvironment of implants. We employed human AMSCs as a practical source for musculoskeletal applications because these cells can be obtained in large quantities, are multipotent, and have trophic paracrine functions. AMSCs were cultured on surgical-grade porous titanium disks as a model for orthopedic implants. We monitored cell/substrate attachment, cell proliferation, multipotency, and differentiation phenotypes of AMSCs upon osteogenic induction. High-resolution scanning electron microscopy and histology revealed that AMSCs adhere to the porous metallic surface. Compared to standard tissue culture plastic, AMSCs grown in the porous titanium microenvironment showed differences in temporal expression for genes involved in cell cycle progression (CCNB2, HIST2H4), extracellular matrix production (COL1A1, COL3A1), mesenchymal lineage identity (ACTA2, CD248, CD44), osteoblastic transcription factors (DLX3, DLX5, ID3), and epigenetic regulators (EZH1, EZH2). We conclude that metal orthopedic implants can be effectively seeded with clinical-grade stem/stromal cells to create a pre-conditioned implant.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054723PMC
http://dx.doi.org/10.1016/j.gene.2016.01.015DOI Listing
May 2016

Multi-disciplinary antimicrobial strategies for improving orthopaedic implants to prevent prosthetic joint infections in hip and knee.

J Orthop Res 2016 Feb 29;34(2):177-86. Epub 2015 Dec 29.

Department of Orthopedic Surgery, Mayo Clinic, 200 1st St SW, Rochester, Minnesota 55905.

Like any foreign object, orthopaedic implants are susceptible to infection when introduced into the human body. Without additional preventative measures, the absolute number of annual prosthetic joint infections will continue to rise, and may exceed the capacity of health care systems in the near future. Bacteria are difficult to eradicate from synovial joints due to their exceptionally diverse taxonomy, complex mechanistic attachment capabilities, and tendency to evolve antibiotic resistance. When a primary orthopaedic implant fails from prosthetic joint infection, surgeons are generally challenged by limited options for intervention. In this review, we highlight the etiology and taxonomic groupings of bacteria known to cause prosthetic joint infections, and examine their key mechanisms of attachment. We propose that antimicrobial strategies should focus on the most harmful bacteria taxa within the context of occurrence, taxonomic diversity, adhesion mechanisms, and implant design. Patient-specific identification of organisms that cause prosthetic joint infections will permit assessment of their biological vulnerabilities. The latter can be targeted using a range of antimicrobial techniques that exploit different colonization mechanisms including implant surface attachment, biofilm formation, and/or hematogenous recruitment. We anticipate that customized strategies for each patient, joint, and prosthetic component will be most effective at reducing prosthetic joint infections, including those caused by antibiotic-resistant and polymicrobial bacteria.
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http://dx.doi.org/10.1002/jor.23068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824296PMC
February 2016

Evaluation of pediatric ATD biofidelity as compared to child volunteers in low-speed far-side oblique and lateral impacts.

Traffic Inj Prev 2014 ;15 Suppl 1:S206-14

a Center for Injury Research and Prevention, Children's Hospital of Philadelphia , Philadelphia , Pennsylvania.

Objective: Motor vehicle crashes are a leading cause of injury and mortality for children. Mitigation of these injuries requires biofidelic anthropomorphic test devices (ATDs) to design and evaluate automotive safety systems. Effective countermeasures exist for frontal and near-side impacts but are limited for far-side impacts. Consequently, far-side impacts represent increased injury and mortality rates compared to frontal impacts. Thus, the objective of this study was to evaluate the biofidelity of the Hybrid III and Q-series pediatric ATDs in low-speed far-side impacts, with and without shoulder belt pretightening.

Methods: Low-speed (2 g) far-side oblique (60°) and lateral (90°) sled tests were conducted using the Hybrid III and Q-series 6- and 10-year-old ATDs. ATDs were restrained by a lap and shoulder belt equipped with a precrash belt pretightener. Photoreflective targets were attached to the head, spine, shoulders, and sternum. ATDs were exposed to 8 low-speed sled tests: 2 oblique nontightened, 2 oblique pretightened, 2 lateral nontightened, 2 lateral pretightened. ATDs were compared with previously collected 9- to 11-year-old (n=10) volunteer data and newly collected 6- to 8-year-old volunteer data (n=7) tested with similar methods. Kinematic data were collected from a 3D target tracking system. Metrics of comparison included excursion, seat belt and seat pan reaction loads, belt-to-torso angle, and shoulder belt slip-out.

Results: The ATDs exhibited increased lateral excursion of the head top, C4, and T1 as well as increased downward excursion of the head top compared to the volunteers. Volunteers exhibited greater forward excursion than the ATDs in oblique nontightened impacts. These kinematics correspond to increased shoulder belt slip-out for the ATDs in oblique tests (ATDs=90%; volunteers=36%). Contrarily, similar shoulder belt slip-out was observed between ATDs and volunteers in lateral impacts (ATDs=80%; volunteers=78%). In pretightened impacts, the ATDs exhibited reduced lateral excursion and torso roll-out angle compared to the volunteers.

Conclusions: In general, the ATDs overestimated lateral excursion in both impact directions, while underestimating forward excursion of the head and neck in oblique impacts compared to the pediatric volunteers. This was primarily due to pendulum-like lateral bending of the entire ATD torso compared to translation of the thorax relative to the abdomen prior to the lateral bending of the upper torso in the volunteers, likely due to the multisegmented spinal column in the volunteers. Additionally, the effect of belt pretightening on occupant kinematics was greater for the ATDs than the volunteers.
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http://dx.doi.org/10.1080/15389588.2014.930832DOI Listing
June 2015
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