Abnormal B-cell development in TIMP-deficient bone marrow

Abstract

Bone marrow (BM) is the primary site of hematopoiesis and is responsible for a lifelong supply of all blood cell lineages. The process of hematopoiesis follows key intrinsic programs that also integrate instructive signals from the BM niche. First identified as an erythropoietin potentiating factor, tissue inhibitor of metalloproteinase (TIMP) protein family has expanded to 4 members and has widely come to be viewed as a classical regulator of tissue homeostasis. By virtue of metalloprotease inhibition, TIMPs not only regulate extracellular matrix turnover but also control growth factor bioavailability. The four mammalian TIMPs possess overlapping enzyme inhibition profiles and have never been studied for their cumulative role in hematopoiesis. Here, we show that TIMPs are critical for post-natal B lymphopoiesis in the BM. TIMP-deficient mice have defective B-cell development arising at the pro-B cell stage. Expression analysis of TIMPless hematopoietic cell subsets pointed to an altered B-cell program in the Lineage−c-Kit+Sca-1+ cell (LSK) fraction. Serial and competitive BM transplants identified a defect in TIMP- deficient HSPCs for B lymphopoiesis. In parallel, reverse BM transplants uncovered the extrinsic role of stromal TIMPs in pro- and pre-B cell development. TIMP-deficiency disrupted CXCL12 localization to LepR+ cells, and increased soluble CXCL12 within the BM niche. It also compromised the number and morphology of LepR+ cells. These data provide new evidence that TIMPs control the cellular and biochemical makeup of the BM niche along with influencing the LSK transcriptional program required for optimal B-lymphopoiesis.

From Marrow to Bone and Fat: Exploring the Multifaceted Roles of Leptin Receptor Positive Bone Marrow Mesenchymal Stromal Cells

“…Tissue inhibitors of metalloproteinases (TIMPs) inhibit the activity of matrix metalloproteinase (MMP). The downregulation of TIMPs increases MMP activity, which cleaves the membrane-bound CXCL12 and solubilizes them, and impairs IL-7 signaling and hampers B cell development [ 57 ].…”

Circulating Biomarkers Associated with the Diagnosis and Prognosis of B-Cell Progenitor Acute Lymphoblastic Leukemia

“…Those cellular processes are intrinsically regulated by signaling pathways, which mainly control transcription factors that triggers leukemogenesis development [ 12 , 24 , 25 , 42 , 43 , 44 , 45 , 46 ]. The most common pathways involved in leukemia pathogenesis are SCF/c-kit receptor, Notch, HOX, Wnt, EPO-induced, CXCL12-CXCR4, JAK-STAT, and PI3K/AKT/mTOR [ 35 , 36 , 47 ] ( Figure 2 ). All the changes generated by leukemogenesis affect various aspects at different cellular levels: genetic, metabolic, and functional.…”