Controlling the Emergence of Hematopoietic Progenitor Cells from Embryonic Stem Cells · fate decisions. Pluripotent stem cells (PSCs) are a valuable tool for research into disease
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Controlling the Emergence of Hematopoietic Progenitor Cells from Pluripotent Stem Cells
by
Kelly Anne Purpura
A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy
Chemical Engineering and Applied Chemistry Collaborative Program: Institute of Biomaterials and Biomedical Engineering
Controlling the Emergence of Hematopoietic Progenitor Cells from Pluripotent Stem Cells
Kelly Anne Purpura
Doctor of Philosophy
Department of Chemical Engineering and Applied Chemistry Collaborative Program: Institute of Biomaterials and Biomedical Engineering
University of Toronto
2010
Abstract
Embryogenesis occurs within a complex and dynamic cellular environment that influences cell
fate decisions. Pluripotent stem cells (PSCs) are a valuable tool for research into disease models
as well as a resource for cell therapy due to their capacity to self-renew and differentiate into all
cell types. Mimicking aspects of the embryonic microenvironment in vitro impacts the resultant
functional cells. The aim of this work was to develop a controlled and scaleable process for the
generation of hematopoietic progenitor cells (HPCs) from embryonic stem cells (ESCs). We
demonstrated with bioreactor-grown embryoid bodies (EBs) that increased HPC generation can
be elicited by decreasing the oxygen tension by a mechanism where vascular endothelial growth
factor receptor 2 (VEGFR2) activation is controlled through competition with the ligand decoy
VEGFR1. This is important as it demonstrates the inherent responsiveness of the developing
hematopoietic system to external forces and influences. We also established a serum-free system
iii
that facilitates directed differentiation, determining 5 ng/ml bone morphogenetic protein-4
(BMP4) with 50 ng/ml thrombopoietin (TPO) could generate 292 ± 42 colony forming cells
(CFC)/5 x 104 cells with early VEGF treatment (25 ng/ml, day 0-5). We also controlled
aggregate size influencing relative endogenous and exogenous growth factor signaling and
modulating mesodermal differentiation; CFC output was optimal when initialized with 100 cell
aggregates. For the first time, we demonstrated efficacy of local growth factor delivery by
producing HPCs with gelatin microparticles (MP). Overall, these design components generate
HPCs in a controlled and reproducible manner using a serum-free bioprocess that couples size
controlled aggregates containing gelatin MPs for localized growth factor release of BMP4 and
TPO with hypoxia to induce endogenous VEGF production. These strategies provide a tunable
platform for developing cell therapies and high density growth, within a bioreactor system, can
be facilitated by hydrogel encapsulation of the aggregates.
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Acknowledgments This body of work did not spring forth in isolation, and I would like to thank all the members of
the Zandstra and collaborating labs for providing aid in the form of discussions, reagents,
protocols, expertise, and help – it was highly appreciated. I would also like to thank my friends
and family for their support, as well as the following funding sources: NSERC, OGS, OGSST,
and SCN. A special thank you goes out to everyone who reminded me one way or another of the
Nike slogan, and got me out of bed in the morning. I also wish to thank my committee members,
Andras Nagy, Molly Shoichet, and William Stanford for their guidance and encouragement.
Lastly, I wish to thank my supervisor, Peter Zandstra for the opportunity and guidance that
brought this work to completion – for painting the big picture, seeing the good in my data, and
for boosting my morale when necessary.
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Table of Contents Acknowledgments.......................................................................................................................... iv
Table of Contents............................................................................................................................ v
List of Tables ................................................................................................................................. ix
List of Figures ................................................................................................................................. x
List of Supplementary Figures...................................................................................................... xii
List of Appendices ....................................................................................................................... xiii
Abbreviations............................................................................................................................... xiv
Soluble Flt-1 Regulates Flk-1 Activation to Control Hematopoietic and Endothelial Development in an Oxygen Responsive Manner......................................................................43
2.3.1 ESC blood and endothelial cell output are correlated with VEGF secretion rates in opposite ways...............................................................................................................52
2.3.2 ESC blood Mutant VEGF receptor ESC lines demonstrate that Flt-1 plays a critical role in oxygen-mediated modulation of HPC..................................................54
2.3.3 Hypoxia influences Flk-1 activation via the secretion of Flt-1 and VEGF .................56
vi
vii
2.3.4 Mimicking the Flt-1 mediated control of ESC fate under normoxic conditions: effects on blood and endothelial cell output ............................................................... 57
2.3.5 Controlling Flk-1 activation of primary E7.5 derived cells alters hematopoietic and endothelial outputs in a manner similar to that observed in EB differentiation... 60
2.3.6 Over-expression of Flt-1-Fc in vivo disrupts vascular and hematopoietic development................................................................................................................ 63
Analysis of the Temporal and Concentration-Dependent Effects of BMP-4, VEGF and Tpo on the Development of Embryonic Stem Cell-Derived Mesoderm and Blood Progenitors in a Defined, Serum-Free Media.............................................................................................. 73
3.3.1 ESC maintenance in N2B27 serum-free defined media ............................................. 81
3.3.2 BMP-4 promotes dose-dependent T and VEGFR-2 expression: differentiation towards hematopoietic progenitor cells in N2B27 serum-free defined media ........... 81
3.3.3 Development of serum-free mesodermal enhancing media........................................ 85
3.3.4 Serum-free differentiation of ESC .............................................................................. 87
3.3.5 Effect of cytokines on hematopoietic progenitor cell development ........................... 89
Endogenous Control and Local Delivery of Inductive Factors to Guide Serum-Free Blood Development from Mouse Pluripotent Stem Cells .................................................................. 98
5.1.4 Transfer of Scaleable Propagation and Differentiation Methods from mESC to a Serum-Free hESC or hiPSC System......................................................................... 143
Appendix A ................................................................................................................................ 147
The Impact of Exogenous Factors .............................................................................................. 147
Chapter 4 Table 1. Primers used for qRT-PCR of the phenotypically sorted cells. ................................... 122
Chapter 5 Table 2. Isoelectric points of various proteins ........................................................................... 130
Appendix A Table 3. Primers used for qRT-PCR: assessing the endoderm potential of d14 plated EBs. .... 154
x
List of Figures Chapter 1 Figure 1.1. Experimental approach to HPC generation from ESCs. ............................................. 6
Figure 1.2. Development of the mouse embryo prior to gastrulation. ........................................... 7
Figure 1.3. Schematic representation of mouse embryonic development. .................................... 9
Figure 1.4. Origins of hematopoiesis and engraftment potential................................................. 12
Figure 1.5. The in vitro EB model. .............................................................................................. 16
Figure 1.6. Parallels between HSC development in the mouse embryo and differentiating ESCs. ....................................................................................................................................................... 22
Figure 1.7. A tuneable microenvironment to facilite EB differentiation. .................................... 42
Chapter 2 Figure 2.1. Hematopoietic progenitor cell (HPC) production, EC development and VEGF secretion is a function of oxygen tension...................................................................................... 53
Figure 2.2. Flt-1 is the major modulator of CFC production and in soluble form (sFlt-1) may impact Flk-1 activation as a result of oxygen concentration. ....................................................... 55
Figure 2.3. Control of Flk-1 activation affects CFC and EC output in a developmental stage-specific manner. ............................................................................................................................ 59
Figure 2.4. Modulation of hematopoietic and endothelial development from primary embryo-derived cells as a function of altering Flk-1 activation and inhibition. ........................................ 62
Figure 2.5. Flt-1-Fc overexpression mimics loss of Flk-1 activation in vivo.............................. 64
Figure 2.6. Schematic of the proposed model.............................................................................. 66
Chapter 3 Figure 3.1. BMP-4 and LIF allow cell expansion and maintain the undifferentiated cell phenotype in N2B27 media. ......................................................................................................... 82
Figure 3.2. Phenotypic expression of developing EBs cultured in N2B27 media supplemented with or without 10 ng/ml BMP-4 or serum control. ..................................................................... 84
Figure 3.3. Removal of B27 and the addition of BME improves the yield of VEGFR-2+ and T-GFP+VEGFR-2+ cells. ................................................................................................................. 86
Figure 3.4. T-GFP and VEGFR-2 expression changes in response to cytokine supplementation of N2BME..................................................................................................................................... 88
Figure 3.5. The cytokine cocktail effects hematopoietic differentiation as measured following eight days of treatment.................................................................................................................. 90
Figure 3.6. Delivery time of VEGF effects hematopoietic CFC output, while early BMP-4 (d0-5) delivery is as effective as continuous treatment (d0-8). ............................................................... 92
Figure 4.3. Endogenous growth factors can be induced using hypoxia and exogenous factors can be delivered locally with gelatin microparticles. ........................................................................ 112
Figure 4.4. Combining local growth factor delivery with hypoxic induction of exogenous factors supports mesodermal development............................................................................................. 115
Figure 5.2. Future methods: gelatin microparticle formation and their incorporation into aggregates. .................................................................................................................................. 141
Appendix A
Figure A.1. The general progression of lineage commitment can be tracked over time. .......... 150
Figure A.2. In response to growth factor cocktail different numbers of initiating cells enhance mesodermal potential. ................................................................................................................. 151
Figure A.3. The cytokine cocktail influences CFC output and endoderm gene induction differently based on the initial aggregate size............................................................................. 152
Figure A.4. Conditioned media can enhance the CFC output of the least inductive conditions...................................................................................................................................................... 155
Figure A.5. Screen of 10 hematopoietic cytokines. ................................................................... 158
Figure A.6. Comparing the hematopoietic progenitors produced with BAW or BVT treatment...................................................................................................................................................... 160
xii
List of Supplementary Figures Chapter 2 Supplementary Figure 1. Gene expression analysis of the expression of VEGF and its receptors during ESC differentiation. ........................................................................................................... 70
Supplementary Figure 2. sFlt-1 in the supernatant.. .................................................................... 71
Supplementary Figure 3. Phosphorylation of Flk-1 in different conditions. ............................... 71
Supplementary Figure 2. Kinetic CFC output is dependent on initial aggregate size ............... 123
Supplementary Figure 3. Aggregate encapsulation is an efficient process ............................... 123
Supplementary Figure 4. BMP4 was released from the gelatin MPs and detected within the embryoid bodies.......................................................................................................................... 124
Supplementary Figure 5. Similar mesodermal phenotypes observed with soluble or microparticle growth factor delivery................................................................................................................. 125
xiii
List of Appendices Appendix A
The Impact of Exogenous Factors .............................................................................................. 147
xiv
Abbreviations 7AAD 7-amino-actinomycin D AGM Aorta-gonad-mesonephros A-P Anterior-posterior Alb/ALB Albumin Afp/αFP Alpha-fetoprotein ARNT Arylhydrocarbon receptor nuclear translocator AVE Anterior visceral endoderm BAW 1 ng/ml BMP4, 2 ng/ml Activin A, 3 ng/ml Wnt3a B27 B27 supplement BL Blast BME β-mercaptoethanol BM Bone marrow BMSC Bone marrow stem cells BMP Bone morphogenetic protein BSA Bovine serum albumin BVT 5 ng/ml BMP4, 25 ng/ml VEGF, 50 ng/ml TPO CAM Cell adhesion molecule CD Cluster of differentiation CDM Chemically defined medium CFC Colony forming cell Cdx4 Caudal-type homeobox transcription factor 4 CFU Colony forming unit CM Conditioned media Cps1 Carbamoyl phosphate synthetase I DA Dorsal aorta Dl-, Dll- Delta- , Delta-like- DMEM Dulbecco’s Modified Eagle Medium DMPS Dimethylpolysiloxane Dpc days post coitum E Embryonic day EB Embryoid body EC Endothelial cell ECM Extracellular matrix EGF Epidermal growth factor ELISA Enzyme-linked immunosorbent assay Epi Epiblast Epo Erythropoietin EryD Erythroid (definitive) EryP Erythroid (primitive) ES Embryonic stem E+/-T+/-P+/-F+/- E-cadherin Brachyury PDGFRα Flk1 marker expression Evx1 Even skipped homeotic gene 1 homolog FACS Fluorescence activated cell sorting FBS Fetal bovine serum FGF Fibroblast growth factor
Interestingly, Flt-1-/- ESCs were completely defective in the hypoxic enhancement of CFC output
(0.7 fold increase, p= 0.05). This data implicates Flt-1 in enhancing CFC generation under
hypoxic conditions.
55 55
56
Figure 2.2. Flt-1 is the major modulator of CFC production and in soluble form (sFlt-1)
may impact Flk-1 activation as a result of oxygen concentration. The CFC capacity of wild
type R1 cells, and their mutant derivatives VEGF-/-, Flt-1-/-, Flk-1-/- was assessed in hypoxia and normoxia
(Ai). The total cell expansion of the parental or mutant R1 cells was independent of oxygen tension (fold
1.0 ± 0.4). 105 cells were seeded on day seven. The CFC capacity of wild type G4 cells and their
derivative Flt1-Fc mutant was assessed in hypoxia and normoxia (Aii). Cell expansion of both the G4
wild type and its mutant varied between normoxia and hypoxia, thus the total CFC for 1000 input ESC
was reported. 5 x 104 cells were seeded on day seven. Significant differences (p < 0.05) are indicated
between hypoxic and normoxic conditions for each cell line (*), between normoxic WT and mutant CFC
production (&), or between hypoxic WT and mutant CFC production (#). Representative FACS plot
demonstrating the Flk-1 isotype control (shaded), and positive Flk-1 expression in hypoxia (solid line)
and normoxia (dashed line) (Bi). Kinetic Flk-1 expression profile in normoxia and hypoxia as measured
by flow cytometric analysis (Bii). Kinetic VEGF and sFlt-1 concentration profiles (Siepmann and Peppas
2001) under normoxia and hypoxia were determined by ELISA, and the calculated ratio of molecules of
VEGF/sFlt-1 is shown (n ≥ 3) (C).
In a second series of studies we used control G4 cells and a derived mutant line, Flt-1-Fc that
over expresses the protein. There was not a significant difference between the G4 parental line
and Flt-1-Fc in normoxia (p=0.13) but in hypoxia Flt-1-Fc generated significantly more CFC
when compared to both the Flt-1-Fc (p=0.002) or G4 line (p=0.03) (Figure 2.2Aii). In sharp
contrast to the reduced CFC output observed relative to wild type with the VEGF-/-, Flt-1-/- and
Flk-1-/- mutants, the Flt-1-Fc ESCs produced significantly more CFC in hypoxia than G4 wild
type controls. Together this data implicates, for the first time, Flt-1 in the oxygen mediated
regulation of blood progenitor cell development.
2.3.3 Hypoxia influences Flk-1 activation via the secretion of Flt-1 and VEGF
The previous results suggest that oxygen concentration may influence the dynamic interaction
between VEGF and its receptors. Gene expression analysis indicates that VEGF, Flt-1 and Flk-1
expression change with time and that VEGF is affected by oxygen concentration (Supplement
Figure 1). To assess these differences at the protein level, we first measured Flk-1 cell-surface
receptor expression using flow cytometry (Figure 2.2Bi). In normoxia, EB Flk-1 expression was
detected on day three, peaked on day five, and then declined for the remainder of the culture
(Figure 2.2Bii). The profile of Flk-1 expression at 4 % O2 was similar in shape to 20 % O2;
57
however, Flk-1 expression peaked one day earlier. The discrepancies between protein and
mRNA measurements for Flk-1 may result from the translation of the gene, or by differences in
the processing and secretion of the extracellular proteins. This suggests that there is a
developmental window that is sensitive to oxygen concentration, during which Flk-1 signaling
may be important.
In contrast to Flk-1 which was detected on the surface of the cells, we could only find Flt-1 upon
analysis of media supernatants. ELISA revealed the production of a soluble form of Flt-1
(sFlt-1), strongly supporting its role as an inhibitor due to its lack of intracellular signal
transduction capacity. Measured values for the concentrations of sFlt-1 are provided in
Supplementary Figure 2. The dynamic competition for the VEGF produced in hypoxia in
contrast to normoxic conditions is best shown by the ratio of VEGF/sFlt-1 (the ratio of the ligand
and its decoy) (Figure 2.2C). The VEGF dimer binds two molecules of receptor (Keyt et al.
1996); we calculated the concentration of protein as the number of molecules of VEGF or sFlt-1
respectively in the bulk media, and assumed that binding occurred in homodimer form. This
ratio (VEGF/sFlt-1) is initially high in hypoxia; but the ratio drops towards one by day 5. In
contrast, in normoxia the ratio is low until day four; after this time the ratio increases and
approaches one. These results are consistent with our earlier results that suggest blood
development proceeds in a VEGF/Flk-1 independent manner in normoxia and that the increase in
blood development during hypoxia proceeds from high VEGF signaling early during culture.
Thus, sFlt-1 may influence cell fate during ESC differentiation via the temporal and
microenvironment dependent control of ligand (VEGF) availability.
2.3.4 Mimicking the Flt-1 mediated control of ESC fate under normoxic conditions: effects on blood and endothelial cell output
We have proposed that sFlt-1 plays a modulating role in the oxygen-mediated enhancement of
blood progenitor generation (and an inverse effect on endothelial cells). Differences between
VEGF and sFlt-1 concentration profiles in hypoxia suggest that CFC generation is enhanced by
early activation of Flk-1, followed by sFlt-1-mediated competitive inhibition of Flk-1 activation.
To further explore and validate the proposed mechanism, Flk-1 activation was controlled in a
time-dependent manner under normoxic conditions using R1 wild type ESCs. Treatments were
provided to either activate (with VEGF) or inhibit Flk-1 signaling (with SU1498) and both HPC
and EC generation were evaluated. Flk-1 activation and SU1498 inhibition was confirmed by
58
immunoprecipitation with Flk-1 and immunoblotting with a phosphorylated tyrosine kinase
antibody (Supplement Figure 3).
As expected, early VEGF treatment (day 0-5) generated more hemogenic mesoderm compared to
the untreated control; HPC frequency and EC growth was 2.3 ± 0.8 and 2.3 ± 0.6-fold higher
respectively (Figure 2.3A). The observation that blood and endothelial cells develop in close
proximity in yolk sac blood islands support a hypothesis that these cells originate from a
common precursor, the hemangioblast (Sabin 1920). An in vitro equivalent of this precursor can
be measured using the blast-colony-forming cell (BL-CFC) assay (Kennedy et al. 1997, Choi et
al. 1998). We confirmed that hypoxia can enhance BL-CFC output (Ramirez-Bergeron et al.
2004) based on colony morphology (Figure 2.3Bi, ii) and that the addition of VEGF to normoxic
cultures had a similar effect (Supplement Figure 4). BL-CFC identity was confirmed with a gene
expression panel, the majority showing CD34 and the lack of brachyury expression characteristic
of BL-CFC (Kennedy et al. 1997, Choi et al. 1998), and functional CFC and EC assays
(Supplement Figure 4B,C). Kinetic analysis of BL-CFC activity in our cultures showed a peak
at day 4-4.5 of differentiation (data not shown). Together this data suggests that VEGF-mediated
signaling (either direct or mediated by hypoxia) acts to increase the hemogenic mesoderm pool
during the first 4-5 days of differentiation.
Figure 2.3. Control of Flk-1 activation affects CFC and EC output in a developmental
stage-specific manner. Comparison of wild type CFC or EC generation in response to treatment
patterns in normoxia. Treatments were normalized with respect to the unsupplemented control media,
and only continuous SU1498 treatment affected cell proliferation (approx. 0.3-fold Control). Treatments
included continuous SU1498 Flk-1 kinase inhibitor (SU0-7), VEGF supplied for the first five days of
culture (V0-5), continuously (V0-7) or from day 5-7 (V5-7), and VEGF for five days followed by
SU1498 (V0-5 SU5-7) as indicated on the x-axis (A). * Indicates a significant difference between the
treated condition and untreated controls (p < 0.02, n ≥ 3); # indicates a significant difference between the
indicated treatment condition and VEGF d0-5 (p < 0.05, n ≥ 3). A representative blast colony is shown
after four days of growth in the blast assay (Bi). Single cells were plated into blast media at
60000 c/35mm plate from d2.5-4.5 EBs. Scale bar = 100 µm. Cells from day 4 EBs cultured in hypoxia
produced more BL-CFC than in normoxia (Bii). Cells were plated at 100000 c/dish and bars indicate
standard deviation of a representative experiment. Representative EC morphology after fixation and
PECAM staining on day seven of the indicated treatments (C). R1 cells were treated for 7 days as
indicated in each of the headings (Ci-vi) while the Flk-1-/- cell line was used as a negative control in
untreated media (D). Scale bar = 500 µm.
59
60
Striking differences in EC outgrowth morphology were also observed as a function of VEGF
activation or inhibition. Baseline levels of EC development were observed in wild type ESCs
cultured in serum (Figure 2.3Ci), while Flk-1-/- ESCs showed little EC development
(Figure 2.3D), a result also seen when wild type ESCs were treated with SU1498 continuously
(Figure 2.3Cii). Highly branched EC networks arose from VEGF-treated cultures with
continuous VEGF supplementation (Figure 2.3Civ), or from days 5-7 only (Figure 2.3Cv). The
presence of VEGF early in culture (day 0-5), followed by Flk-1 inhibition by SU1498 resulted in
the generation of only compact areas of ECs (Figure 2.3Cvi).
2.3.5 Controlling Flk-1 activation of primary E7.5 derived cells alters hematopoietic and endothelial outputs in a manner similar to that observed in EB differentiation
Thus far our results have been limited to ESC differentiation. Although an interesting and useful
model system, we next sought to determine if the stage dependent control of Flk-1 activation
could elicit similar fate changes in primary cells. We established ex vivo cultures from wild type
E7.5 embryos. This developmental stage corresponds to day 4-5 EBs (Keller 2005), and allowed
us to evaluate fate decisions in response to Flk-1 activation or inhibition. CFC development
from this cell source consisted primarily of monocyte and erythroid colonies (Figure 2.4A). A
dose-dependent enhancement in CFC number per embryonic-derived input cell was obtained
from the loosely-adherent layer of embryonic cells treated with Flk-1 antagonists
(Figure 2.4Bi,ii). In contrast, exogenous VEGF resulted in a significant dose-dependent
suppression of CFC output (Figure 2.4Biii). Strikingly, an opposite effect was seen in the
analysis of EC development where the Flk-1 antagonists (mFlt-1-Fc and SU1498) suppressed EC
output (Figure 2.4Ci,ii), while VEGF enhanced EC output while (Figure 2.4Biii). Visual
inspection showed that VEGF enhanced outgrowth and branching from EC colonies, whereas the
mrFlt-1-Fc and SU1498 treatments repressed this growth (Figure 2.4D). The differences in the
branching morphology of the ECs in response to altered Flk-1 signaling is consistent with earlier
observations of vessel formation in the EB system (Roberts et al. 2004).
61
Figure 2.4. Modulation of hematopoietic and endothelial development from primary
embryo-derived cells as a function of altering Flk-1 activation and inhibition. Cells from
E7.5 embryos were cultured on OP9-GFP feeders for five days. Representative myeloid and erythroid
colonies from E7.5 cultures are shown (A). Cells were treated with mrFlt-1-Fc (Bi), SU1498 (Bii), or
VEGF (Biii) at various concentrations to modulate development in a manner similar to the EB system.
CFC capacity, in comparison to untreated controls, was enhanced by treatment with Flt-1-Fc (0.1, 0.3, 1.0
Figure A.5. Screen of 10 hematopoietic cytokines. The initial concentration of the 10 cytokines
was measured in freshly prepared N2BME (A). LSC differentiation was initiated in N2BME serum-free
media and EBs were treated with different combinations of 5 ng/ml BMP4, 25 ng/ml VEGF and 50 ng/ml
TPO for 7 days. The media was conditioned between d5-7 and then compared to the base media to detect
differences (B). Briefly, cells were treated continuously with B, BT, or BVT; treated for 5 days with B or
BT before changing to differentitaition media without factors or treated for 5 days with BVT before
anging to either B or BT supplementation. As continuous treatment with BVT was not expected to
on was not included in part (B) which highlights the
tokines upregulated by the hemogenic treatments. The stacked fold-change (C) and the CFC output (D)
of all the factors for each treatment are also shown.
ch
enhance hematopoietic CFC formation this conditi
cy
B B BT BT BTV BTV BTV0
20
30
40
10
BT T BTV 0 BT 0 B D0-5:D5-7:
Fold
bas
e m
edia
-N2B
ME
Treatment
IL4 IL2 TNFα IL5 INFγ GM-CSF IL12 IL6 IL10 IL1b
Treatment
Day 0-5Day 5 -8
CFC
per
5x1
0 4
cells
100
200
300
400
BV BVB
BVBT
BTBT
BVTBT
B BTT
Treatment
Day 0-5Day 5 -8
CFC
per
5x1
0 4
cells
100
200
300
400
BVBV BVBBVB
BVBTBVBT
BTBTBTBT
BVTBTBVTBT
BB BTTBTT
159
inally, to extend the analysis of the cellular response of the 10 cell aggregate to BAW and the
100 cell aggregate to BVT treatment the phenotypes were analyzed on day 9 for CD41,
e
F
CD34/45, and CD150, with the day 7 CFC results shown for reference (Figure A.6A,B).
moxia with BVT treatment resulted in a population that was
ixed) than CD41, and that was ~4% and ~3% positive for CD150,
ositive for CD45. Strikingly, the BAW treated
inimal expression of CD34/45 and CD150. This
re immature progenitor population than BVT induction. To see
e conditions were transferred to hypoxia and treated
in incubation with trypsin. The phenotypes were
s were removed from the media on day 12
for the different treatments and representativ
colonies are shown (Figure A.6D). Trypsinization seemed to enhance the phenotypic markers of
10 BAW, but not for the BVT/HBT conditions, although this did not translate to CFC capacity.
Similar numbers of CFC were seen from the 10 BAW condition seeded day 7 and 14, however,
there was a higher proportion of GEMMs on d14 which may reflect a population shift from
CD41 to CD45. For the 100 HBT condition, CFC capacity was reduced approximately 90%.
Overall, the 100 HB(V)T condition appears promising and may contain ESC-derived HSCs that
may be detected in a SCID model.
Hypoxia with BT treatment and nor
higher in CD34/45 (m
respectively. Nearly all CD150 cells were also p
cells were 30% positive for CD41 and had m
suggests that BAW induces a mo
whether the cells could continue maturing, th
with BT either directly or following a 2 m
assessed again on day 12 and 14, and the factor
(Figure A.6C). The CFC assay was seeded on d14
Figure A.6. Comparing the hematopoietic progenitors produced with BAW or BVT
treatment. To explore the outputs of the different treatment conditions 100 cell aggregates were either
treated with BVT in normoxia or with BT in hypoxia, while 10 cell aggregates were treated with BAW in
normoxia. The hypoxic condition was started 24 h after aggregation and the cytokines were provided
from day 2-4. Day 7 EBs were plated in a CFC assay (A), and the cell phenotypes were assessed for
CD41, CD34/45, and CD150 on day 9 (B) prior to moving all conditions to hypoxia for an additional 5
days. From day 9-12 the conditions were treated with BT either directly or following 2 minutes in a
trypsin-EDTA solution. The experimental timeline is shown at the top. The cell phenotypes were
assessed on day 12 and 14 (C) and plated in a CFC assay on day 14 (D). Representative colonies from
the three conditions are also shown.
160
100HBT 100BVT 10BAW0
10
20
30
40
% p
ositi
ve
Day 9 CD41+ CD34+/45+ CD150+ CD34+/45+CD150+
100HBT 100BVT 10BAW0
10
20
% p
ositi
ve
Day 12Transfer to hypoxia d9Treat with BT d9-12EB EB+2min trypsin
CD41+ CD34+ CD45+ CD150+
100HBT 100BVT 10BAW0
10
20
% p
ositi
ve
Day 14Transfer to hypoxia d9Treat with BT d9-12EB EB+2min trypsin
CD41+ CD44+ CD45+ CD150+
NS
0
50
100
150
200
250
100 HBT 100 BVT 10 BAW
CFC
/ 50
000
d7 c
ells
0
50
100
150
200
250
100 HBT 100 BVT 10 BAW
Treatment [d0-2] (transfer to hypoxia d9-14)
CFC
/ 50
000
d14
cells
Treat EB directlyTrypsinize EB - 2 min
Day 9-12: BT100 HBT
100 BVT
10 BAW
D
Time [day] 0
Treatment BAW
Seed CFCFACS Analysis
7
Seed CFCFACS Analysis
14
FACS Analysis
3.75
Spin-EB formation
9 12
Analyze CFC
212
100
BVTBT
10
Normoxia
Hypoxia
FACS Analysis
}Hypoxia
}Time [day] 0
Treatment BAW
Seed CFCFACS Analysis
7
Seed CFCFACS Analysis
14
FACS Analysis
3.75
Spin-EB formation
9 12
Analyze CFC
212
100
BVTBT
10
Normoxia
Hypoxia
FACS Analysis
}Hypoxia
}}
C
B A
161
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162
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