Mechanoresponsive stem cells acquire neural crest fate in jaw regeneration.
Correlation of payor status and pediatric transfer for acute appendicitis
Journal of Surgical Research
Management of Chronic Wounds-2018.
2018; 320 (14): 1481–82
Peritoneal Dialysis Is Feasible as a Bridge to Combined Liver-Kidney Transplant.
Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis
; 38 (1): 63–65
During both embryonic development and adult tissue regeneration, changes in chromatin structure driven by master transcription factors lead to stimulus-responsive transcriptional programs. A thorough understanding of how stem cells in the skeleton interpret mechanical stimuli and enact regeneration would shed light on how forces are transduced to the nucleus in regenerative processes. Here we develop a genetically dissectible mouse model of mandibular distraction osteogenesis-which isa process that is used in humans to correct an undersized lower jawthat involves surgically separating the jaw bone, whichelicits new bone growth in the gap. We use this model to show that regions of newly formed bone are clonally derived from stem cells that reside in the skeleton. Using chromatin and transcriptional profiling, we show that these stem-cell populations gain activity within the focal adhesion kinase (FAK) signalling pathway, and that inhibiting FAK abolishes new bone formation. Mechanotransduction via FAK in skeletal stem cells during distraction activates a gene-regulatory program and retrotransposons that are normally active in primitive neural crest cells, from which skeletal stem cells arise during development. This reversion to a developmental state underlies the robust tissue growth that facilitates stem-cell-based regeneration of adult skeletal tissue.
View details for PubMedID 30356216
Wounds Inhibit Tumor Growth In Vivo.
Annals of surgery
Patients with combined liver and kidney failure may remain on dialysis for years while awaiting simultaneous liver-kidney transplantation (SLKT). The role of peritoneal dialysis (PD) in patients with advanced liver and kidney failure awaiting SLKT remains to be defined. We present our single-institution experience with PD in cirrhotics, 3 of whom went on to receive successful SLKT. Patients initiated in our PD program between 2006 and 2016 who had both liver and kidney failure were identified. Medical and dialysis records were reviewed retrospectively. Outcomes included mortality, transplantation status, hospitalizations, need for large-volume paracentesis (LVP), peritonitis rates, PD treatment longevity, and albumin level. Twelve patients with combined liver and kidney failure were treated in our PD program. No patients died and 3 patients received SLKT. Four patients remain listed for transplantation. There was no need for LVP after initiating dialysis. The rate of peritonitis was 0.2 events per patient per year, most commonly due to coagulase-negative Staphylococcus Our data illustrate that PD is a viable bridging therapy for patients with liver and kidney failure who await SLKT.
View details for PubMedID 29311195
Wound healing and fibrosis: current stem cell therapies.
2019; 59 (S1): 884–92
OBJECTIVE: The aim of this study was to determine the interaction of full thickness excisional wounds and tumors in vivo.SUMMARY OF BACKGROUND DATA: Tumors have been described as wounds that do not heal due to similarities in stromal composition. On the basis of observations of slowed tumor growth after ulceration, we hypothesized that full thickness excisional wounds would inhibit tumor progression in vivo.METHODS: To determine the interaction of tumors and wounds, we developed a tumor xenograft/allograft (human head and neck squamous cell carcinoma SAS/mouse breast carcinoma 4T1) wound mouse model. We examined tumor growth with varying temporospatial placement of tumors and wounds or ischemic flap. In addition, we developed a tumor/wound parabiosis model to understand the ability of tumors and wounds to recruit circulating progenitor cells.RESULTS: Tumor growth inhibition by full thickness excisional wounds was dose-dependent, maintained by sequential wounding, and relative to distance. This effect was recapitulated by placement of an ischemic flap directly adjacent to a xenograft tumor. Using a parabiosis model, we demonstrated that a healing wound was able to recruit significantly more circulating progenitor cells than a growing tumor. Tumor inhibition by wound was unaffected by presence of an immune response in an immunocompetent model using a mammary carcinoma. Utilizing functional proteomics, we identified 100 proteins differentially expressed in tumors and wounds.CONCLUSION: Full thickness excisional wounds have the ability to inhibit tumor growth in vivo. Further research may provide an exact mechanism for this remarkable finding and new advances in wound healing and tumor biology.
View details for PubMedID 30829705
Doxycycline Reduces Scar Thickness and Improves Collagen Architecture.
Annals of surgery
Scarring is a result of the wound healing response and causes tissue dysfunction after injury. This process is readily evident in the skin, but also occurs internally across organ systems in the form of fibrosis. Stem cells are crucial to the innate tissue healing response and, as such, present a possible modality to therapeutically promote regenerative healing while minimizing scaring. In this review, the cellular basis of scaring and fibrosis is examined. Current stem cell therapies under exploration for skin wound healing and internal organ fibrosis are discussed. While most therapeutic approaches rely on the direct application of progenitor-type cells to injured tissue to promote healing, novel strategies to manipulate the scarring response are also presented. As our understanding of developmental and stem cell biology continues to increase, therapies to encourage regeneration of healthy functional tissue after damage secondary to injury or disease will continue to expand.
View details for PubMedID 30737822
Author Correction: Genetic dissection of clonal lineage relationships with hydroxytamoxifen liposomes.
2018; 9 (1): 4411
OBJECTIVE: To investigate the effects of local doxycycline administration on skin scarring.BACKGROUND: Skin scarring represents a major source of morbidity for surgical patients. Doxycycline, a tetracycline antibiotic with off-target effects on the extracellular matrix, has demonstrated antifibrotic effects in multiple organs. However, doxycycline's potential effects on skin scarring have not been explored in vivo.METHODS: Female C57BL/6J mice underwent dorsal wounding following an established splinted excisional skin wounding model. Doxycycline was administered by local injection into the wound base following injury. Wounds were harvested upon complete wound closure (postoperative day 15) for histological examination and biomechanical testing of scar tissue.RESULTS: A one-time dose of 3.90 mM doxycycline (2 mg/mL) within 12 hours of injury was found to significantly reduce scar thickness by 24.8% (P < 0.0001) without compromising tensile strength. The same effect could not be achieved by oral dosing. In doxycycline-treated scar matrices, collagen I content was significantly reduced (P = 0.0317) and fibers were favorably arranged with significantly increased fiber randomness (P = 0.0115). Common culprits of altered wound healing mechanics, including angiogenesis and inflammation, were not impacted by doxycycline treatment. However, engrailed1 profibrotic fibroblasts, responsible for scar extracellular matrix deposition, were significantly reduced with doxycycline treatment (P = 0.0005).CONCLUSIONS: Due to the substantial improvement in skin scarring and well-established clinical safety profile, locally administered doxycycline represents a promising vulnerary agent. As such, we favor rapid translation to human patients as an antiscarring therapy.
View details for PubMedID 30585822
Genetic dissection of clonal lineage relationships with hydroxytamoxifen liposomes.
2018; 9 (1): 2971
In the original version of this Article, the authors inadvertently omitted Elizabeth A. Brett, who contributed to the generation of the histology figures, from the author list.This has now been corrected in both the PDF and HTML versions of the Article.
View details for PubMedID 30341306
Renal artery aneurysm associated with Leber hereditary optic neuropathy
Journal of Vascular Surgery Cases and Innovative Techniques
2018; 4 (1): 5-7
The evolving relationship of wound healing and tumor stroma
Targeted genetic dissection of tissues to identify precise cell populations has vast biological and therapeutic applications. Here we develop an approach, through thepackaging and delivery of 4-hydroxytamoxifen liposomes (LiTMX), that enables localized induction of CreERT2 recombinase in mice. Our method permits precise, in vivo, tissue-specific clonal analysis with both spatial and temporal control. This technology is effective using mice with both specific and ubiquitous Cre drivers in a variety of tissue types, under conditions of homeostasis and post-injury repair, and is highly efficient for lineage tracing and genetic analysis. This methodology is directly and immediately applicable to the developmental biology, stem cell biology and regenerative medicine, and cancer biology fields.
View details for PubMedID 30061668
The stroma in solid tumors contains a variety of cellular phenotypes and signaling pathways associated with wound healing, leading to the concept that a tumor behaves as a wound that does not heal. Similarities between tumors and healing wounds include fibroblast recruitment and activation, extracellular matrix (ECM) component deposition, infiltration of immune cells, neovascularization, and cellular lineage plasticity. However, unlike a wound that heals, the edges of a tumor are constantly expanding. Cell migration occurs both inward and outward as the tumor proliferates and invades adjacent tissues, often disregarding organ boundaries. The focus of our review is cancer associated fibroblast (CAF) cellular heterogeneity and plasticity and the acellular matrix components that accompany these cells. We explore how similarities and differences between healing wounds and tumor stroma continue to evolve as research progresses, shedding light on possible therapeutic targets that can result in innovative stromal-based treatments for cancer.
View details for DOI 10.1172/jci.insight.99911