The migration of hematopoietic progenitors from the fetal liver to the fetal bone marrow: Lessons learned and possible clinical applications  Jesús Ciriza, Heather Thompson, Raffi Petrosian, Jennifer O. Manilay, Marcos E. García-Ojeda  Experimental Hematology  Volume 41, Issue 5, Pages 411-423 (May 2013) DOI: 10.1016/j.exphem.2013.01.009 Copyright © 2013 ISEH - Society for Hematology and Stem Cells Terms and Conditions

Figure 1 Identification of LT-HSCs with SLAM markers in the FL and adult BM by confocal microscopy. Immunohistochemistry of FL at 14.5 dpc and adult BM at 4 weeks was performed. LT-HSCs were identified as CD150+CD48−CD41−Lin−. CD150 is shown in red; CD48, CD41, and lineage markers are shown in green. Blue represents nuclei staining with TOTO-3 dye. Only cells stained positively in red with blue nuclei and staining negatively in green were considered LT-HSCs. Experimental Hematology 2013 41, 411-423DOI: (10.1016/j.exphem.2013.01.009) Copyright © 2013 ISEH - Society for Hematology and Stem Cells Terms and Conditions

Figure 2 Model of FBM HSC migration towards the nascent endosteal niche. The BM microenvironment forms during embryonic development, accommodating LT-HSC by day 17.5 of gestation. Following extravasation through bone vessels, HSCs are guided toward the primary center of endosteal ossification by gradients of SDF-1 and Ca2+. HSCs secrete metalloprotease (MMP-2 and MMP9) at their leading edge, degrading extracellular matrix components (Col4A) and facilitating their migration. Simultaneously, HSC synthesize collagen and secrete metalloprotease inhibitors (TIMP2), helping to repair the extracellular matrix. Experimental Hematology 2013 41, 411-423DOI: (10.1016/j.exphem.2013.01.009) Copyright © 2013 ISEH - Society for Hematology and Stem Cells Terms and Conditions

Figure 3 Models of FBM HSC niche formation. Under the static niche model, the BM niche, once formed, remains relatively constant through adult life. In contrast, under the dynamic niche model, the newly established FBM niche constantly evolves to accommodate the needs of the organism throughout life. Experimental Hematology 2013 41, 411-423DOI: (10.1016/j.exphem.2013.01.009) Copyright © 2013 ISEH - Society for Hematology and Stem Cells Terms and Conditions

Figure 4 The mechanism of migration of FL HSCs to the FBM and its potential applications. Understanding the mechanisms in the migration of HSCs from FL to FBM would shed light on the specific molecules need to be activated in ESC-HPs to support or improve their engraftment. The left portion of the figure shows relative expression of molecules important in migration and homing, where a light purple color equates low concentration and dark purple represents higher concentration of the respective marker. The middle arrow represents a developmental time course, starting at early embryonic development and finishing at adult stages. Fetal liver HSCs are located in the middle of the time course. ESC-HPs display similar phenotype to early, prefetal liver development HP stages. Modifying their developmental phenotype so that it resembles later developmental stages such as the FL, could increase ESC-HP homing and engrafting capacities. (For interpretation of the reference to color in this figure legend, the reader is referred to the web version of this article.) Experimental Hematology 2013 41, 411-423DOI: (10.1016/j.exphem.2013.01.009) Copyright © 2013 ISEH - Society for Hematology and Stem Cells Terms and Conditions