Stromal SPARC contributes to the detrimental fibrotic changes associated with myeloproliferation whereas its deficiency favors myeloid cell expansion

Abstract

In myeloid malignancies, the neoplastic clone outgrows normal hematopoietic cells toward BM failure. This event is also sustained by detrimental stromal changes, such as BM fibrosis and osteosclerosis, whose occurrence is harbinger of a dismal prognosis. We show that the matricellular protein SPARC contributes to the BM stromal response to myeloproliferation. The degree of SPARC expression in BM stromal elements, including CD146 ؉ mesenchymal stromal cells, correlates with the degree of stromal changes, and the sever-

Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

“…Within the spleen parenchyma, myeloid cells populating the red pulp have been shown to assist B cells in a T cell-independent fashion by releasing trophic and prosurvival factors ( 27 ). Furthermore, our recent fi ndings linked stromal SPARC defi ciency to myeloid cell proliferation in the bone marrow ( 18 ), and the observed myeloid cell skewing in the presence of autoimmunity ( 28 ) suggested that myeloid cell expansion and localization may be altered in lpr/lpr/Sparc −/− . Combining FACS, immunohistochemistry ( IHC), and immunofl uorescence analyses, we observed increases in spleen myeloid cells and myeloid precursors (LK, GMP) in Fas-mutant mice, and these populations were further expanded in the absence of SPARC, confi rming that the Sparc −/− background is permissive for myeloproliferative signals ( Fig.…”

“…Outputs of the automated image analysis relative to the eight microphotographs obtained from the two TMA spots of each case were averaged to obtain the SPARC expression value for that case. Routine hematoxylin and eosin (H&E), Masson's trichrome, and Gomori's silver staining were performed as previously described ( 18 ).…”

“…SPARC is a nonstructural pleiotropic matricellular protein that is a key regulator of tissue stroma remodeling in physiologic conditions and pathologic settings, including cancer and parenchymal fi brosis ( 16 ). SPARC also plays a role in the profound changes that occur in the tissue architecture of solid and hematologic neoplasms ( 17,18 ). SPARC produced by innate immune cells infl uences the cross-talk between cancer cells and the ECM at the invasive edge of primary tumors and regulates proinfl ammatory TNF production in response to tissue damage ( 16 ).…”

“…SPARC produced by innate immune cells infl uences the cross-talk between cancer cells and the ECM at the invasive edge of primary tumors and regulates proinfl ammatory TNF production in response to tissue damage ( 16 ). Moreover, bone marrow stroma-derived SPARC was reported to regulate the expansion of myeloid cell populations under myeloproliferative stress ( 18 ). In SLO, SPARC is a determinant of correct germinal center assembly and lymphocyte traffi cking during adaptive immune responses ( 19 ).…”

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

“…Furthermore, it remains elusive how heterogeneous the stromal population is, and whether there is an overlap of Gli1 + and LepR + cells. Another open question is how the identified cell populations compare with CD146 + , SPARC‐expressing cells, which also were shown to react to myeloproliferative stimuli 43, 44. Future single‐cell resolution studies will shed light on this interesting topic.…”