Human Bone Marrow Stromal Cells Lose Immunosuppressive and Anti-inflammatory Properties upon Oncogenic Transformation

Abstract

SummaryBecause of their immunomodulatory properties, human bone marrow stromal cells (hBMSCs) represent promising stem cells for treatment of immune disorders. hBMSCs expansion precedes their clinical use, so the possibility that hBMSCs undergo spontaneous transformation upon long-term culture should be addressed. Whether hBMSCs retain immunosuppressive and anti-inflammatory properties upon oncogenic transformation remains unknown. Using sequentially mutated hBMSCs and spontaneously transformed hBMSCs, we report that, upon oncogenic transformation, hBMSCs lose immunosuppressive and anti-inflammatory properties in vitro and in vivo. Transcriptome profiling and functional assays reveal immune effectors underlying the loss of immunomodulation in transformed hBMSCs. They display a proinflammatory transcriptomic signature, with deregulation of immune and inflammatory modulators and regulators of the prostaglandin synthesis. Transformed hBMSCs lose their capacity to secrete the immunosuppressive prostacyclins prostaglandin E2 (PGE2) and PGI2 but produce proinflammatory thromboxanes. Together, the immunoregulatory profile adopted by hBMSCs largely depends on intrinsic genetic-molecular determinants triggered by genomic instability/oncogenic transformation.

Detailed Characterization of Mesenchymal Stem/Stromal Cells from a Large Cohort of AML Patients Demonstrates a Definitive Link to Treatment Outcomes

“…Using carboxyfluorescein succinimidyl ester (CFSE) dilution assays to monitor cell division, we found that AML-derived BM-MSCs suppressed the proliferation of phytohemagglutinin (PHA)-stimulated human peripheral blood mononuclear cells (PBMCs) irrespective of the molecular subgroup (Figure 3A). In line with previous studies, the level of immunosuppression (measured as non-proliferating PHA-stimulated lymphocytes) was 44% ± 20% and 14% ± 8% for HD-derived BM-MSCs and tMSCs, respectively (Figure 3A; Funes et al., 2007, Rodriguez et al., 2014, Sanchez et al., 2011). Intriguingly, AML-derived BM-MSCs had a more robust immunosuppressive potential (74% ± 18% for LR-AML, 55% ± 20% for IR-AML and 66% ± 16% for HR-AML; p < 0.05) than HD-derived BM-MSCs.

Figure 3In Vitro Immunosuppressive and Anti-Inflammatory Properties of BM-MSCs from HDs and AML Patients(A) Left: level of immunosuppression measured as percentage of CFSE + non-proliferating cells.

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IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

“…In order to recapitulate a BM stroma milieu, 1 × 10 5 HL60 (n = 31 mice) or MOLM-13 (n = 33 mice) cells were intra-BM transplanted into non-irradiated NSG mice together with 3 × 10 5 irradiated BM-MSCs. 25,27 HL60 AML grafts were monitored by BM aspiration and mice were randomized into treatment groups when graft was >1% in the contralateral BM (~2–3 weeks post-transplant). For MOLM-13 AML grafts, mice were randomized for treatment 3 days after intra-BM transplant due to its aggressiveness.…”

Prospective isolation of resident adult human mesenchymal stem cell population from multiple organs

“…It is thought that MSCs respond to inflammation and have specific roles in immune regulation, lymphopoiesis, and bone homeostasis [70,71]. These reports used cultured MSCs; accordingly, it is unknown whether the response is similar under physiological conditions.…”