Replacement of wounded skin requires the initially florid cellular response to abate and even regress as the dermal layer returns to a relatively paucicellular state. The signals that direct this "stop and return" process have yet to be deciphered. CXCR3 chemokine receptor and its ligand CXCL11/IP-9/I-TAC are expressed by basal keratinocytes and CXCL10/IP-10 by keratinocytes and endothelial cells during wound healing in mice and humans. In vitro, these ligands limit motility in dermal fibroblasts and endothelial cells. To examine whether this signaling pathway contributes to wound healing in vivo, full-thickness excisional wounds were created on CXCR3 wild-type (؉/؉) or knockout (؊/؊) mice. Even at 90 days, long after wound closure, wounds in the CXCR3 ؊/؊ mice remained hypercellular and presented immature matrix components. The CXCR3 ؊/؊ mice also presented poor remodeling and reorganization of collagen, which resulted in a weakened healed dermis. This in vivo model substantiates our in vitro findings that CXCR3 signaling is necessary for inhibition of fibroblast and endothelial cell migration and subsequent redifferentiation of the fibroblasts to a contractile state. These studies establish a pathophysiologic role for CXCR3 and its ligand during wound repair. Skin wound repair is a complex, highly orchestrated event consisting of an early hypercellular infiltrate that resolves over time, with loss of most of the regenerativephase dermal fibroblasts and vascular conduits.1 This reversion of the dermal cellularity is necessary for the maturation and strengthening of the matrix, which when lacking, leads to chronic wounds.2 This leaves open the question of which signals define both the transition from regeneration to resolution and the cellular involution that accompanies these changes.Wound repair requires the ordered immigration of fibroblasts into the provisional matrix and keratinocytes over this matrix. This immigration and replacement of the tissue appears to be under the influence of both soluble factors secreted first by platelets and then by inflammatory cell infiltrates, and also matrix components produced by these cells and the immigrated fibroblasts and endothelial cells. Among the latter, tenascin-C and thrombospondins seem to play a major role and thereby mark the immature, regenerative phase of wound healing. [3][4][5] These influence the functionality of the vasculogenesis by acting, directly or indirectly, through growth factor receptors.6,7 These events involve a degree of cellular dedifferentiation to enable migration and proliferation. During the remodeling phase, sufficient cells have migrated into the provisional dermal matrix to mature this structure and across the missing epidermal gap to re-establish a keratinocyte covering. These cells then differentiate into synthetic fibroblasts to produce a mature collagen I-rich dermis or basal keratinocytes primed to differentiate vertically. Interestingly, a fully repaired dermis is paucicellular compared with the regenerative phase, implying a sig...
The lower-hoop-strength, higher-profile tantalum Strecker stent is affected by vascular wall recoil and evokes a greater degree of neointima formation than the lower-profile, higher-hoop-strength Palmaz stent and Wallstent. Medial atrophy is pronounced outside the latter two stents. The rigid Palmaz stent can penetrate through the vascular wall in flexing arteries.
G207 is a multimutated, conditionally replicating herpes simplex virus type 1 (HSV-1) that is currently in clinical trial for patients with malignant glioma. G207 exhibits an efficient oncolytic activity in tumor cells, yet minimal toxicity in normal tissue when injected into the brains of HSV-susceptible mice or nonhuman primates. In this study, we evaluated the shedding and biodistribution of clinical-grade G207 after intracerebral inoculation (3 x 10(7) pfu) in four New World owl monkeys (Aotus nancymae). Using PCR analyses and viral cultures, neither infectious virus nor viral DNA was detected from tear, saliva, or vaginal secretion samples at any time point up to 1 month postinoculation. Analyses of tissues obtained at necropsy at 1 month from two of the four monkeys, plus one monkey inoculated with laboratory-grade G207 (10(9) pfu) 2 years earlier, showed the distribution of G207 DNA restricted to the brain, although infectious virus was not isolated. Histopathology revealed normal brain tissues including the sites of inoculation. A measurable increase of serum anti-HSV antibody titer was observed in all monkeys, as early as 21 days postinoculation. The results ascertain the safety of G207 in the brain and indicate that strict biohazard management may not be required for G207-treated patients.
BackgroundTransplantation of mesenchymal stem cells (MSC) has been proposed to improve wound healing. However, as these cells only transiently survive in the implantation site, the mechanisms underlying this beneficial healing response are associated with restorative paracrine effects of MSC matricellular factors on resident stromal cells. However, this requires that the recipient has a robust reservoir of viable cells. Here, we examine the influence of MSCs on the behavior of cotransplanted fibroblasts, in a manner to provide augmented cellular reserve to debilitated individuals, specifically focusing on matrix remodeling following in-vivo wounding.MethodsUsing a Hylan-A dermal filler hydrogel containing collagen I and tenascin-C for delivery and increased survival of transplanted cells, we find that cotransplantation of MSCs with fibroblasts reduces scarring.ResultsTransplanted xenogeneic MSCs augmented fibroblast proliferation, migration, and extracellular matrix deposition critical for wound closure, and reduced inflammation following wounding. MSCs also corrected matrix remodeling by CXCR3-deficient fibroblasts which otherwise led to hypertrophic scarring. This effect was superior to MSC or fibroblast transplantation alone.ConclusionsTaken together, these data suggest that MSCs, even if eventually rejected, transplanted with fibroblasts normalize matrix regeneration during healing. The current study provides insight into cellular therapies as a viable method for antifibrotic treatment and demonstrates that even transiently engrafted cells can have a long-term impact via matrix modulation and education of other tissue cells.
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