Dermatopontin in Bone Marrow Extracellular Matrix Regulates Adherence but Is Dispensable for Murine Hematopoietic Cell Maintenance

Abstract

SummaryThe hematopoietic marrow microenvironment is composed of multiple cell types embedded in an extracellular matrix (ECM). We have explored marrow ECM using mass spectrometry and found dermatopontin (DPT), a small non-collagenous ECM protein, to be present. We found that DPT cooperates with other ECM proteins to promote hematopoietic cell adherence in vitro on plastic as well as OP9 stromal cells. We generated constitutional DPT−/− mice that were viable and had no peripheral lympho-hematopoietic abnormalities. The composition of the marrow of wild-type and DPT−/− mice was equivalent in terms of cellularity, CFU-C, LSK (Lineage−, SCA-1+, KIT+), and LSK-SLAM (LSK, CD48−, CD150+) frequencies. These data suggest that DPT fosters adherence but is not required for steady-state hematopoiesis in vivo. There are likely overlapping cellular adhesion mechanisms that can compensate to maintain the hematopoietic niche in the absence of DPT.

An irradiated marrow niche reveals a small non-collagenous protein mediator of homing, dermatopontin

“…It was hypothesized that DPT was acting to help tether HSC to the stromal layer and perhaps allow for improved contact between HSC and growth factors produced by stroma augmenting paracrine signals. We also previously observed that DPT can directly bind HSPC and modulate HSPC adherence to OP9 murine stroma cells 28 . Conversely, in the context of HSPC adherence to endothelial cells, we found the reverse effectthe presence of DPT led to reduced adherence.…”

“…We focused on genes expressed at the cell membrane or extracellularly secreted versus the transcription factors as the former would be more likely modulate intrinsic HSPC activity. One particular gene found to be elevated in irradiated niche cells was dermatopontin (dpt) a small (23 kDa) non-collagenous extracellular matrix (ECM) protein that we have previously described in the murine marrow ECM 28 . Other prior work has shown that murine DPT can play a positive role in HSPC ex vivo culture expansion 29 ; though, we have shown DPT knockout mice have no steady state hematopoietic deficits and do have increased peripheral HSPC mobilization capacity suggesting a role in cell trafficking 28 .…”

“…One particular gene found to be elevated in irradiated niche cells was dermatopontin (dpt) a small (23 kDa) non-collagenous extracellular matrix (ECM) protein that we have previously described in the murine marrow ECM 28 . Other prior work has shown that murine DPT can play a positive role in HSPC ex vivo culture expansion 29 ; though, we have shown DPT knockout mice have no steady state hematopoietic deficits and do have increased peripheral HSPC mobilization capacity suggesting a role in cell trafficking 28 . DPT has been previously described as being present in the skin, bone, fibroblasts, and plasma [30][31][32] .…”

“…We created a DPT knockout (KO) mouse to more precisely define the role of DPT in hematopoietic cell biology. Mice were viable and without obvious deficits in lifespan or fertility and were without intrinsic hematopoietic defects 28 . Homing experiments in DPT KO mice revealed bone marrow mononuclear cells (BMMC) migrated 60% more efficiently to the marrow in DPT KO mice compared to wild-type (WT) mice assessed16 hours after adoptive transfer, and donor LSK migrated 50% more efficiently (Figure 6A, p = 0.029 and p = 0.038, respectively).…”

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“…Our molecular analyses also show the potential of EA to modulate over 1,600 BM genes that are mainly related to extracellular matrix receptor interaction, B cell and toll-like receptors signaling, and the p53 and NF-kB pathways. Indeed, the extracellular matrix is critical to hematopoiesis and the response of hematopoietic cells to neurotransmitters and growth factors ( 24 , 80 ). For instance, fibronectin is important for the adhesion and proliferation of hematopoietic and erythroid progenitors ( 81 ), whereas adiponectin can inhibit myelomonocytic cell expansion ( 82 ) and Col1a1 and Col1a2 are produced by BM stromal cells to define BM hematopoietic niche microenvironment ( 83 , 84 ).…”