Expression of cytokine and extracellular matrix mRNAs in fetal hepatic stellate cells

Abstract

In mouse fetal liver, hepatoblasts, sinusoidal endothelial cells and macrophages (or erythroblastic islands) promote differentiation and proliferation of hematopoietic cells through cell-cell interactions and secretion of cytokines and extracellular matrix factors. Until now, we have had little knowledge of the hematopoietic cytokines or extracellular matrix mRNAs expressed in hepatic stellate cells. Using p75 neurotrophin receptor (p75NTR) to mark this cell population, we sorted 12.5, 14.5 and 16.5 dpc hepatic stellate cells and analyzed expression of cytokines and extracellular matrix mRNAs. Among cytokines, insulin-like growth factor 2 (Igf2) was highly expressed at all three stages analyzed. The extracellular matrix molecule fibronectin (Fn1) was highly expressed in 12.5 dpc cells, whereas vitronectin (Vtn) was highly expressed in 14.5 and 16.5 dpc hepatic stellate cells. Among liver cells, Igf2 was predominantly expressed in hepatoblast-like cells at all three stages examined, suggesting that hepatoblast-like cells are an essential part of the niche that maintains homeostasis of hematopoietic cells in embryonic mouse liver. Defining these expression patterns could facilitate our understanding of cross talk between cytokine and extracellular matrix molecules in hepatic stellate cells and benefit research in developmental hematopoiesis as well as the study of liver biology.

Crosstalk Between the Hepatic and Hematopoietic Systems During Embryonic Development

“…Other typical hepatoblast markers are listed in Table 1. Prox1,Alb,Afp,Ck8,Ck18,Ck19,Met,Hnf6,Oc2,Hnf4a,Ttr,Foxm1,Foxa2,Tbx3,Dlk1,Lgr5,Epcam,Cdh1,Trgb1,Itga6,Liv2,Prom1, Anpep Tanimizu et al, 2003;Tan et al, 2017) E-Cadherin + (Nitou et al, 2002;Nierhoff et al, 2005) EpCAM + DLK1 + (Tanaka et al, 2009) Liv2…”

“…Indeed, several cytokines/chemokines/growth factors are important for HSC proliferation, maintenance and survival, namely KITL, FLT3L, insulin growth factor (IGF), angiopoietin-3, angiopoietin-like 2, Wnt family growth factors, Ephrin2a, CSF1, EPO, CXCL12, and IL-6 -reviewed in Sauvageau et al (2004). In FL, some of these cytokines are expressed by hepatoblasts or other stromal cells, such as stellate cells or pericytes (see Table 2 and Figure 4; Charbord and Moore, 2005;Chou and Lodish, 2010;Khan et al, 2016;Tan et al, 2017).…”

“…Stromal regulation of hematopoiesis has been proposed by many and early studies of co-culture of hematopoietic progenitors with either FL fibroblast or epithelial-stromal cell lines showed erythroid and myeloid support (Tsai et al, 1986;Hata et al, 1993). More than 200 FL stromal cell lines have been developed and tested for maintenance or expansion of HSCs, however, only a few were able to maintain their repopulating activity (Tan et al, 2017) c-Kit (CD117) (Yarden et al, 1987) BM HSC survival and self-renewal (Barker, 1994;Miller et al, 1997) ANGPTL2…”

“…Nestin + cells (Khan et al, 2016) PirB (Zheng et al, 2012) BM HSC proliferation (Zhang et al, 2006) ANGPTL3 DLK1 + hepatoblasts (Chou and Lodish, 2010) PirB (Zheng et al, 2012) BM HSC maintenance (Zheng et al, 2011) BM HSC proliferation (Zhang et al, 2006) FLT3L Stellate cells (Tan et al, 2017) Flt3 (CD135) (Matthews et al, 1991) FL HSPC proliferation (Lyman et al, 1993) TPO DLK1 + hepatoblasts (Chou and Lodish, 2010;Sugiyama et al, 2011;Brouard et al, 2017) Stellate cells (Tan et al, 2017) MPL (TPO-R, CD110) (Vigon et al, 1992) FL HSC survival and proliferation (Petit-Cocault et al, 2007) BM HSC quiescence (Nakamura et al, 2007;Qian et al, 2007) CSF1 Stellate cells (Tan et al, 2017) Csf-1 Receptor (Guilbert and Stanley, 1980) Commitment to macrophage lineage (Rieger et al, 2009) EPO DLK1 + hepatoblasts (Sugiyama et al, 2011) Stellate cells (Tan et al, 2017) EPO receptor (Sawyer et al, 1987) Proliferation and differentiation of FL erythroid progenitors (Lin et al, 1996) CXCL12 Dlk1 + hepatoblasts (Chou and Lodish, 2010) Nestin + cells (Khan et al, 2016) Stellate cells (Kubota et al, 2007) CXCR4 (Bleul et al, 1996) FL and FBM B-cell lymphopoiesis and FBM myelopoiesis (Nagasawa et al, 1996) BM HSC engraftment post-transplantation (Lai et al, 2014;McDermott et al, 2015) FL HSC retainment (Ara et al, 2003) BM HSC retainment (Sugiyama et al, 2006) IL-7 VCAM1 + ALCAM + DLK1 + hepatoblasts …”

Regulated differentiation of stem cells into an artificial 3D liver as a transplantable source

“…HSCs can fulfill some of the functions of MSCs, such as adipocytes or osteocytes differentiation. 33,34 Thus far, only Coll et al 35 reported that they could obtain HSC-like cells from newborn male fibroblastsderived human iPSC by mimicking embryonic development; those cells closely resemble primary human HSCs at the transcriptional, cellular, and functional levels and possess a gene expression profile between that of quiescent and activated HSCs.…”