The Supportive Role of Lymph Node Mesenchymal Stromal Cells in Follicular Lymphoma Involves the PITX1-hTERT-Podoplanin Axis.

Abstract

The microenvironment within lymph nodes plays a pivotal role in the pathogenesis of follicular lymphoma (FL), a malignancy characterized by the accumulation of neoplastic B cells. Here, we report that human FL lymph node mesenchymal stromal cells (FLSCs) display surface protein expression profiles consistent with the standard phenotypic criteria for human mesenchymal stromal/stem cells (MSCs), yet exhibit reduced mesenchymal differentiation capability. FLSCs did not show the typical immunomodulatory protein expression patterns observed in fibroblastic reticular cells, marginal reticular cells, or follicular dendritic cells, as they expressed chemokine (C-X-C motif) ligand 13 and podoplanin but lacked chemokine (C-C motif) ligand 19 and complement receptor 1/2. Functionally, FLSCs exhibited superior FL cell survival-supportive capability in cocultures compared with bone marrow MSCs. This supportive effect was reduced when the cell culture inserts were used. In addition, this supportive capability was accompanied by reduced levels of B-cell-supportive soluble factors such as interleukin-6, regardless of the presence of cell culture inserts. Thus, both cell-cell contact-dependent and -independent mechanisms are involved in this process. Comprehensive transcriptomic analysis revealed that transcription factor paired-like homeodomain 1 (PITX1) is downregulated in FLSCs. Given that PITX1 regulates human telomerase reverse transcriptase (hTERT) transcription, FLSCs exhibited longer telomeres and a higher population-doubling capacity than MSCs. Furthermore, FLSCs expressed elevated podoplanin, whereas MSCs did not. Notably, hTERT-transfected MSCs also showed increased podoplanin expression, suggesting a positive association between hTERT and podoplanin. In summary, our findings indicate that FLSCs deviate from classical MSCs in their differentiation potential and instead exhibit a protumorigenic phenotype. This phenotype supports FL cell survival and is potentially mediated by an aberrant PITX1-hTERT-podoplanin signaling axis. These results highlight the critical role of FLSCs in the FL lymph node microenvironment, with implications for understanding tumor-supportive niches in FL pathogenesis.