compromised mice. Four weeks later, IL-6 neutralizing antibody was injected locally into the transplant, twice a week (5 mg/ injection) for 4 weeks. Our results showed that intra-lesional injection with IL-6 neutralizing antibody significantly reduced the size of KPC-generated transplants (Figure 6J). These results provide further evidence that IL-6 plays an important role in both initiation and maintenance of KPC transplants, suggesting a potential anti-scarring therapeutic effect. Since our KPC transplant studies were carried out in athymic nude (nu/nu) mouse which might be devoid of functional T lymphocytes [70], we transplanted KPCs using hydrogel with and without IL-6 into immunocompromised mice adapted by CD4+CD25- T-lymphocytes (Na¨ıve T) infusion. Our results showed that boosting T cell function in immunocompromised mice significantly promoted growth of KPC transplants, in the presence or absence of IL-6 (Figure 7A). Immunofluorescence studies showed an increased expression of IL-17 by CD4 positive- T-lymphocytes, which was further enhanced by IL-6 treatment (Figure 7B). The increased IL-17 expression was further confirmed by ELISA assay (Figure 7C). All together, our results suggest that the IL-17/IL-6 axis may function to maintain the highly elevated IL-6 level in the distinct keloid niche with abilities to regulate key stem cell functions such as hTERT and Oct-4 expression, thus contributing to the formation of the benign keloid growth. Discussion Unlike a more precise topographical organization of epithelial stem cells in skin epithelium, the dermal layer harbors Oct-4 and SSEA-4 positive cells that are randomly distributed in the reticular dermis, interspersed among thick ECM, as seen abundantly resided in keloid tissues. The relatively abundant expression of two major markers for embryonic and mesenchymal stem cells Niche-Driven Overgrowth of KPC [54,64,65], Oct-4 and SSEA-4, in keloid as compared to normal skin tissues, suggests the presence of postnatal stem cells in pathologic scar and may contribute to its persistent growth. In the last few decades, several groups have shown that multipotent precursor cells can be generated from different normal adult human tissues [64–66,71,72], and may share common biological properties, including the expression profile of various cell surface markers and embryonic transcription markers as well as their multipotent differentiation capabilities [10,66,71]. Thus, adult stem cells may play an essential role in growth, homeostasis and regeneration of many tissues. However, up to date, how stem cells contribute to pathologic diseases remains largely unknown. Recently, several studies have reported the isolation and characterization of precursor cells from normal rodent and human normal skin dermis (SKPs) [54–56], and recently, mesenchymal-like stem cells from keloid scars (KMLSCs) [73]. However, to our knowledge, no study has determined whether SKPs differ from precursor cells derived from their aberrant scars, specifically their in vivo self-renewal and regenerative capacities, and more importantly, whether the pathological niche driven by the inflammatory cytokines of the keloid scar affect their growth and differentiation. In this study, we have isolated and characterized a population of keloid derived precursor cells, termed KPCs, which share some stem cell properties as KMLSCs [73], including self-renewal, clonogene- city and multiple differentiation capacities. However, KPCs inherently expressed higher levels of pluripotent-specific tran- scription factors Oct-4 and telomerase activity, increased clonogenicity and proliferative capabilities as compared to SKPs derived from the same donor. Based on these distinct stem cell properties, KPCs may represent the benign tumor-like stem cell counterpart of SKPs which might contribute, at least in part, to the high proliferative state in keloid tumor. Figure 7. Effect of T cell infusion on in vivo growth of KPC-generated transplants. A, Size and volume of KPC transplants (mean6SEM). Activated CD4+CD252 T lymphocytes were infused at 16106/mouse through the tail vein two days before KPC transplants. KPCs were mixed with hydrogel with or without IL-6 and transplanted subcutaneously for 8 weeks. * P,0.05; ** P,0.01. B, Dual-color immunostaining for mouse CD4 (red) and IL-17 (green) using paraffin-embedded sections of KPC transplants. Scale bars, 50 mm. (C) Tissue lysates were prepared from the transplant tissues, and IL-17 expression was analyzed by ELISA (mean6SEM). * P,0.05, ** P,0.01. The results are representative of five independent experiments using KPCs and the matched SKPs from different patient donors. doi:10.1371/journal.pone.0007798.g007 PLoS ONE | www.plosone.org 12 November 2009 | Volume 4 | Issue 11 | e7798