925 HUMAN FETAL LIVER PROGENITOR CELLS AND THEIR IN-VIVO DIFFERENTIATION

In the group of patients (n = 21, mean age 54 ± 5.8 years) with chronic lower limb ischemia stage IIB who were non-liable for reconstructiverestoration surgery, we have established positive clinical effects of local transplantation of human fetal liver progenitor cells. Complex examination following 1, 3, 6 and 12 months after transplantation included duplex scanning of limb arteries, x-ray contrast arteriography and laser Doppler flowmetry as well as measuring pain-free walking and evaluating life quality based on individual questionnaire data.Owing to the transplant “Cryopreserved human fetal liver progenitor cells” the patients demonstrated stable increase of life quality index and pain-free walking as well as improvement of general health allowing assign them to the group of patients with lower ischemia stage, quicker social rehabilitation and lesser risk of disabling surgery (р < 0.05). Also, there were observations of improved microcirculation in the ischemic extremities owing to activation of endothelium-independent mechanisms of vasodilatation, reduced myotonus and neurotonus of the pre-capillaries and improved endothelium-dependent influence on the microhaemodynamic and, hence, an increased reserve capillary blood flow (p < 0.05).Analysis of the obtained results indicates prospects and effectiveness of using fetal liver cells transplantation in the patients who are not liable for surgical reconstruction of the vascular bed.

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Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance

Blood ◽

10.1182/blood-2010-04-281071 ◽

2010 ◽

Vol 116 (17) ◽

pp. 3197-3207 ◽

Cited By ~ 80

Author(s):

Kirsteen J. Campbell ◽

Mary L. Bath ◽

Marian L. Turner ◽

Cassandra J. Vandenberg ◽

Philippe Bouillet ◽

...

Keyword(s):

Progenitor Cells ◽

Progenitor Cell ◽

Fetal Liver ◽

Cytotoxic Agents ◽

Hematopoietic Stem ◽

Stem And Progenitor Cells ◽

Fetal Liver Cells ◽

Follicular Lymphomas ◽

The Impact

Abstract Diverse human cancers with poor prognosis, including many lymphoid and myeloid malignancies, exhibit high levels of Mcl-1. To explore the impact of Mcl-1 overexpression on the hematopoietic compartment, we have generated vavP-Mcl-1 transgenic mice. Their lymphoid and myeloid cells displayed increased resistance to a variety of cytotoxic agents. Myelopoiesis was relatively normal, but lymphopoiesis was clearly perturbed, with excess mature B and T cells accumulating. Rather than the follicular lymphomas typical of vavP-BCL-2 mice, aging vavP-Mcl-1 mice were primarily susceptible to lymphomas having the phenotype of a stem/progenitor cell (11 of 30 tumors) or pre-B cell (12 of 30 tumors). Mcl-1 overexpression dramatically accelerated Myc-driven lymphomagenesis. Most vavP-Mcl-1/ Eμ-Myc mice died around birth, and transplantation of blood from bitransgenic E18 embryos into unirradiated mice resulted in stem/progenitor cell tumors. Furthermore, lethally irradiated mice transplanted with E13 fetal liver cells from Mcl-1/Myc bitransgenic mice uniformly died of stem/progenitor cell tumors. When treated in vivo with cyclophosphamide, tumors coexpressing Mcl-1 and Myc transgenes were significantly more resistant than conventional Eμ-Myc lymphomas. Collectively, these results demonstrate that Mcl-1 overexpression renders hematopoietic cells refractory to many cytotoxic insults, perturbs lymphopoiesis and promotes malignant transformation of hematopoietic stem and progenitor cells.

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33. Cryosensitivity of hematopoietic and mesenchymal stem/progenitor cells derived from human fetal liver

Cryobiology ◽

10.1016/j.cryobiol.2006.10.034 ◽

2006 ◽

Vol 53 (3) ◽

pp. 381-382

Author(s):

Yuri A. Petrenko ◽

Nataliya G. Skorobogatova ◽

Rhodri E. Jones ◽

Alexander Y. Petrenko

Keyword(s):

Progenitor Cells ◽

Fetal Liver ◽

Human Fetal Liver

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Unique Differentiation Programs of Human Fetal Liver Stem Cells Shown Both In Vitro and In Vivo in NOD/SCID Mice

Blood ◽

10.1182/blood.v94.8.2686.420k15_2686_2695 ◽

1999 ◽

Vol 94 (8) ◽

pp. 2686-2695 ◽

Cited By ~ 42

Author(s):

Franck E. Nicolini ◽

Tessa L. Holyoake ◽

Johanne D. Cashman ◽

Pat P.Y. Chu ◽

Karen Lambie ◽

...

Keyword(s):

Cord Blood ◽

Fetal Liver ◽

Scid Mice ◽

Human Cord Blood ◽

Human Fetal Liver ◽

Human Erythropoietin ◽

Erythroid Precursors ◽

Lower Ratio

Comparative measurements of different types of hematopoietic progenitors present in human fetal liver, cord blood, and adult marrow showed a large (up to 250-fold), stage-specific, but lineage-unrestricted, amplification of the colony-forming cell (CFC) compartment in the fetal liver, with a higher ratio of all types of CFC to long-term culture-initiating cells (LTC-IC) and a lower ratio of total (mature) cells to CFC. Human fetal liver LTC-IC were also found to produce more CFC in LTC than cord blood or adult marrow LTC-IC, and more of the fetal liver LTC-IC–derived CFC were erythroid. Human fetal liver cells regenerated human multilineage hematopoiesis in NOD/SCID mice with the same kinetics as human cord blood and adult marrow cells, but sustained a high level of terminal erythropoiesis not seen in adult marrow-engrafted mice unless exogenous human erythropoietin (Epo) was injected. This may be due to a demonstrated 10-fold lower activity of murine versus human Epo on human cells, sufficient to distinguish between a differential Epo sensitivity of fetal and adult erythroid precursors. Examination of human LTC-IC, CFC, and erythroblasts generated either in NOD/SCID mice and/or in LTC showed the types of cells and hemoglobins produced also to reflect their ontological origin, regardless of the environment in which the erythroid precursors were generated. We suggest that ontogeny may affect the behavior of cells at many stages of hematopoietic cell differentiation through key changes in shared signaling pathways.

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Migratory path of definitive hematopoietic stem/progenitor cells during zebrafish development

Blood ◽

10.1182/blood-2007-01-069005 ◽

2007 ◽

Vol 109 (12) ◽

pp. 5208-5214 ◽

Cited By ~ 94

Author(s):

Hao Jin ◽

Jin Xu ◽

Zilong Wen

Keyword(s):

Progenitor Cells ◽

Fetal Liver ◽

Embryo Cell ◽

Migration Route ◽

Hematopoietic Stem ◽

Hematopoietic Organ ◽

Blood Island ◽

Adult Kidney ◽

Definitive Hematopoiesis

Abstract The development of vertebrate definitive hematopoiesis is featured by temporally and spatially dynamic distribution of hematopoietic stem/progenitor cells (HSPCs). It is proposed that the migration of definitive HSPCs, at least in part, accounts for this unique characteristic; however, compelling in vivo lineage evidence is still lacking. Here we present an in vivo analysis to delineate the migration route of definitive HSPCs in the early zebrafish embryo. Cell-marking analysis was able to first map definitive HSPCs to the ventral wall of dorsal aorta (DA). These cells were subsequently found to migrate to a previously unappreciated organ, posterior blood island (PBI), located between the caudal artery and caudal vein, and finally populate the kidney, the adult hematopoietic organ. These findings demonstrate that the PBI acts as an intermediate hematopoietic organ in a manner analogous to the mammalian fetal liver to sustain definitive hematopoiesis before adult kidney hematopoiesis occurs. Thus our study unambiguously documents the in vivo trafficking of definitive HSPCs among developmentally successive hematopoietic compartments and underscores the ontogenic conservation of definitive hematopoiesis between zebrafish and mammals.

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Long-term ex vivo expansion of human fetal liver primitive haematopoietic progenitor cells in stroma-free cultures

British Journal of Haematology ◽

10.1046/j.1365-2141.2002.03873.x ◽

2002 ◽

Vol 119 (3) ◽

pp. 792-802 ◽

Cited By ~ 8

Author(s):

Rowayda Peters ◽

Serge Leyvraz ◽

Eveline Faes-van't Hull ◽

Philippe Jaunin ◽

Stefan Gerber ◽

...

Keyword(s):

Progenitor Cells ◽

Ex Vivo ◽

Fetal Liver ◽

Ex Vivo Expansion ◽

Human Fetal Liver

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Integrin alpha 6 Is Essential for Fetal Hematopoietic Progenitor, but Not Fetal Stem Cell Homing to Bone Marrow.

Blood ◽

10.1182/blood.v106.11.1387.1387 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1387-1387

Author(s):

Hong Qian ◽

Sten Eirik W. Jacobsen ◽

Marja Ekblom

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Progenitor Cells ◽

Progenitor Cell ◽

Fetal Liver ◽

Hematopoietic Stem ◽

Stem And Progenitor Cells ◽

Integrin Alpha 6

Abstract Homing of transplanted hematopoietic stem cells (HSC) in the bone marrow (BM) is a prerequisite for establishment of hematopoiesis following transplantation. However, although multiple adhesive interactions of HSCs with BM microenviroment are thought to critically influence their homing and subsequently their engraftment, the molecular pathways that control the homing of transplanted HSCs, in particular, of fetal HSCs are still not well understood. In experimental mouse stem cell transplantation models, several integrins have been shown to be involved in the homing and engraftment of both adult and fetal stem and progenitor cells in BM. We have previously found that integrin a6 mediates human hematopoietic stem and progenitor cell adhesion to and migration on its specific ligands, laminin-8 and laminin-10/11 in vitro (Gu et al, Blood, 2003; 101:877). Furthermore, integrin a6 is required for adult mouse HSC homing to BM in vivo (Qian et al., Abstract American Society of Hematology, Blood 2004 ). We have now found that the integrin a6 chain like in adult HSC is ubiquitously (>99%) expressed also in fetal liver hematopoietic stem and progenitor cells (lin−Sca-1+c-Kit+, LSK ). In vitro, fetal liver LSK cells adhere to laminin-10/11 and laminin-8 in an integrin a6b1 receptor-dependent manner, as shown by function blocking monoclonal antibodies. We have now used a function blocking monoclonal antibody (GoH3) against integrin a6 to analyse the role of the integrin a6 receptor for the in vivo homing of fetal liver hematopoietic stem and progenitor cells to BM. The integrin a6 antibody inhibited homing of fetal liver progenitors (CFU-C) into BM of lethally irradiated recipients. The number of homed CFU-C in BM was reduced by about 40% as compared to the cells incubated with an isotype matched control antibody. To study homing of long-term repopulating stem cells, BM cells were first incubated with anti-integrin alpha 6 or anti-integrin alpha 4 or control antibody, and then injected intravenously into lethally irradiated primary recipients. After three hours, BM cells of the primary recipients were analysed by competitive repopulation assay in secondary recipients. Blood analysis up to 16 weeks after transplantation showed that no reduction of stem cell reconstitution from integrin a6 antibody treated cells as compared to cells treated with control antibody. In accordance with this, fetal liver HSC from integrin a6 gene deleted embryos did not show any impairment of homing and engraftment in BM as compared to normal littermates. These results suggest that integrin a6 plays an important developmentally regulated role for homing of distinct hematopoietic stem and progenitor cell populations in vivo.

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UCP2 Modulates Cell Proliferation through the MAPK/ERK Pathway during Erythropoiesis and Has No Effect on Heme Biosynthesis

Blood ◽

10.1182/blood.v112.11.5372.5372 ◽

2008 ◽

Vol 112 (11) ◽

pp. 5372-5372

Author(s):

Alvaro A Elorza ◽

Brigham B Hyde ◽

Hanna Mikkola ◽

Sheila Collins ◽

Orian S Shirihai

Keyword(s):

Cell Proliferation ◽

Progenitor Cells ◽

Fetal Liver ◽

Mitochondrial Protein ◽

Erythroid Progenitor ◽

Heme Synthesis ◽

Erythroid Progenitor Cells ◽

Deficient Mice

Abstract UCP2, an inner membrane mitochondrial protein, has been implicated in bioenergetics and Reactive Oxygen Species (ROS) modulation. UCP2 has been previously hypothesized to function as a facilitator of heme synthesis and iron metabolism by reducing ROS production. While UCP2 has been found to be induced by GATA1 during erythroid differentiation its role in erythropoiesis in vivo or in vitro has not been reported thus far. Here we report on the study of UCP2 role in erythropoiesis and the hematologic phenotype of UCP2 deficient mouse. In vivo we found that UCP2 protein peaks at early stages of erythroid maturation when cells are not fully committed in heme synthesis and then becomes undetectable at the reticulocyte stage. Iron incorporation into heme was unaltered in erythroid cells from UCP2 deficient mice. While heme synthesis was not influenced by UCP2 deficiency, mice lacking UCP2 had a delayed recovery from chemically induced hemolytic anemia. Analysis of the erythroid lineage from bone marrow and fetal liver revealed that in the UCP2 deficient mice the R3 (CD71high/Ter119high) population was reduced by 24%. The count of BFU-E and CFU-E colonies, scored in an erythroid colony assay, was unaffected, indicating an equivalent number of early erythroid progenitor cells in both UCP2 deficient and control cells. Ex-vivo differentiation assay revealed that UCP2 deficient c-kit+ progenitor cells expansion was overall reduced by 14% with population analysis determining that the main effect is at the R3 stage. No increased rate of apoptosis was found indicating that expansion rather than cell death is being compromised. Reduced expansion of c-kit+ cells was accompanied by 30% reduction in the phosphorylated form of ERK, a ROS dependent cytosolic regulator of cell proliferation. Analysis of ROS in UCP2 null erythroid progenitors revealed altered distribution of ROS resulting in 14% decrease in cytosolic and 32% increase in mitochondrial ROS. Restoration of the cytosolic oxidative state of erythroid progenitor cells by the pro-oxidant Paraquat reversed the effect of UCP2 deficiency on cell proliferation in in vitro differentiation assays. Together, these results indicate that UCP2 is a regulator of erythropoiesis and suggests that inhibition of UCP2 function may contribute to the development of anemia.

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