Fetal liver: an ideal niche for hematopoietic stem cell expansion

Abstract

Fetal liver (FL) is an intricate and highly vascularized hematopoietic organ, which can support the extensive expansion of hematopoietic stem cells (HSCs) without loss of stemness, as well as of the downstream lineages of HSCs. This powerful function of FL largely benefits from the niche (or microenvironment), which provides a residence for HSC expansion. Numerous studies have demonstrated that the FL niche consists of heterogeneous cell populations that associate with HSCs spatially and regulate HSCs functionally. At the molecular level, a complex of cell extrinsic and intrinsic signaling network within the FL niche cells maintains HSC expansion. Here, we summarize recent studies on the analysis of the FL HSCs and their niche, and specifically on the molecular regulatory network for HSC expansion. Based on these studies, we hypothesize a strategy to obtain a large number of functional HSCs via 3D reconstruction of FL organoid ex vivo for clinical treatment in the future.

Towards Mimicking the Fetal Liver Niche: The Influence of Elasticity and Oxygen Tension on Hematopoietic Stem/Progenitor Cells Cultured in 3D Fibrin Hydrogels

“…We initially tried to measure E12.5 FL, but this tissue was too soft and fragile, thus making slicing difficult. E14.5 FL tissue could be handled more easily and was also appropriate, as HSC expansion occurs in the FL between E12.5 and E16 [ 8 ]. For sectioning the tissue, an agarose gel was used according to an established methodology [ 48 , 49 ].…”

“…During mammalian development, HSCs emerge from multiple regions, including the yolk sac, aorta-gonad-mesonephros (AGM), and placenta [ 3 ]. At around E11.5 of murine development or E28 in humans [ 4 , 5 , 6 ], HSCs colonize the fetal liver (FL), a highly vascularized organ that serves as the niche site of hematopoiesis during embryogenesis [ 7 , 8 ]. HSCs interact with other niche cells such as hepatoblasts [ 9 , 10 ], endothelial cells [ 11 , 12 ], and mural cells [ 4 , 7 ] that produce growth factors and cytokines important for HSC expansion and differentiation, including among others, stem cell factor (SCF), FMS-related tyrosine kinase 3 ligand (FLT3-L), and insulin like growth factor 2 (IGF-2) [ 13 , 14 , 15 ].…”

“…In mice, hematopoietic stem/progenitor cells (HSPCs) (containing both HSCs and HPCs) are identified by the surface markers Lin − /Sca + /cKit + (LSK), while additional markers like the so-called Signaling Lymphocyte Activated Molecule (SLAM) markers (CD150 + and CD48 − ) are used to distinguish HSCs (LSK-SLAM cells) from HPCs [ 21 ]. Shortly before birth, HSCs migrate to the bone marrow (BM), serving as the main niche site for adult hematopoiesis [ 3 , 8 ]. One important difference between FL-derived HSCs (FL-HSCs) and BM-derived HSCs (BM-HSCs) is that FL-HSCs are characterized by a much higher self-renewal and repopulation ability compared to BM-HSCs [ 22 ].…”

Alleviation of acute radiation-induced bone marrow failure in mice with human fetal placental stromal cell therapy

“…The liver seems to support hematopoiesis only in early fetal development [ 44 ]. But in spite of the stressful pancytopenia following TBI, we could not detect EMH in the liver in any of the experimental groups tested.…”

Stem cell therapy in autism: recent insights

“…Donor women and fetal samples were tested for bacterial, fungal, and viral infections and parasites. CD34+ HSCs were extracted from fetal liver (a powerful niche for HSCs) 91 and brain and in vitro expanded. Colony-forming units and neurosphere formation were checked.…”