Keratinocyte Growth Factor (KGF) Is Required for Post-Natal Thymic Regeneration.

KGF is a fibroblast growth factor family member (FGF-7) that mediates epithelial cell proliferation and differentiation in a variety of tissues, including thymic epithelial cells. Recent studies have demonstrated that KGF administration (before conditioning) to the recipients of allogeneic bone marrow transplantation (BMT) can enhance T cell and thymic reconstitution. Therefore, we studied the role of KGF on T cell development under normal and stress conditions (such as irradiation) by using KGF (−/−) mice in experimental murine models. Phenotypic analysis of KGF (−/−) mice at varying ages demonstrated that the bone marrow, thymus and lymph node cellularity and the cell distribution among KGF (−/−), wild type (WT) and KGF (+/−) mice (6–11 weeks of age) were similar. However, splenic cellularity and splenic T cell numbers were slightly lower than WT and littermate controls. KGF (−/−) mice are more vulnerable to sublethal irradiation (450–600 cGy) and a more than six fold decrease was found in thymic cellularity when analyzed on day 28 after irradiation, whereas there was no delay in the erythroid, myeloid and platelet recovery after irradiation.

We used bone marrow transplantation models to assess the relative contribution of KGF produced by thymocytes or thymic epithelial cells during thymic regeneration after irradiation. T cell reconstitution was impaired in syngeneic or allogeneic KGF (−/−) BMT recipients in comparison to littermate controls but there was no difference in the distribution of thymocyte subsets or splenic T cell content. The recipients of KGF (−/−) bone marrow had decreased thymic and splenic cellularity after allogeneic BMT. These data demonstrate that both donor and host derived KGF play a role in thymic regeneration. Finally, KGF administration to young and old mice (10 month old) enhanced thymopoiesis when analyzed 28 days after KGF administration. Pre-BMT KGF administration to the recipients of syngeneic and allogeneic BMT also resulted in a 2–6 fold increase in the thymic cellularity compared to the control group.

We conclude that KGF produced by both thymocytes and epithelial cells is not required for normal and post-natal thymic development, but plays a role in post-natal thymic regeneration after irradiation. These data support the potential use of KGF to protect or restore thymic damage after chemo/radiotherapy.