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Liver and bioengineering
Jean-Charles Duclos-Vallée
Centre Hépato-Biliaire
Paul-Brousse Hospital
Microtechnology and
applications in liver bioengineering
Microatterning
Co-culture
Encapsulation
Bioartificial/
Transplantable
bioengineered liver
Drug screening
Disease modelling
Microtechnology and
applications in liver bioengineering
Micropatterning
Co-culture
Encapsulation
Bioartificial/
Transplantable
bioengineered liver
Drug screening
Disease modelling
Microfluidics/
On chip devices
Biomaterials
Biomaterials
2D
Cell culture
Two main types of devices
Artificial Bio Artificial
Living component
A Necessity !
Figaro S, Pereira U, …, Legallais C et al. Int J Organs 2017
Global representation of the differentiation
protocol of hiPSCs into hepatocytes and
encapsulation into alginate beads
CHIR,	
Activin	A,	
LY	
FGF2,	
BMP4,	
FGF4,	HGF	
Definitive	
endoderm	(DE)	
	
hiPSCs	
	
Hepatoblasts	
(iHBs)	
	
Spheroid	
	
HGF,	OSM,	Dex,	SB,	CE,	Vk	
iHBs	spheroid	encapsulation	and	
hepatocyte	differentiation		 Encapsulated	
spheroids	
(E-3D)	
Day	10-11	
iHB	self-
aggregation	
iHBs	differentiation		
Day 26
Day 20
Day 16
Day 11
500 µm 500 µm 500 µm 500 µm
Encapsulation
Day	10	
500 µm
Morphology of encapsulated spheroids
From Marwa Hussein
Distribution of PLL and elastic modulus of
the surface
PLL
Permeability of empty beads
(coated or not with PLL) to
fluorescent markers (albumin,
IgG, nanoparticles of different
diameters)
Distribution of PLL and elastic modulus of the
surface
PLL
Permeability of empty beads
(coated or not with PLL) to
fluorescent markers (albumin, IgG,
nanoparticles of different
diameters)
Metabolic activities of cells in
alginate‐PLL beads, measured on
Day 14, over 6 h' incubation in
equivalent pathological plasma
medium
Ammonia
detoxification rate
Lactate
detoxification rate
Albumin
production
Towards a functional
artificial liver
From Université Technologique de Compiègne
Definition of organoid: in vitro 3D
cellular cluster derived from tissue-
resident stem/progenitor cells,
embryonic stem cells (ESCs) or
induced pluripotent stem cells
(iPSCs) that recapitulates the
functionality of the tissue of origin
Lancaster	MA	and	Knoblich	JA.	Science	2014	
Huch	M	and	Koo	BK.	Development	2015
Organogenesis	and	stages		
for	organoid	progenitor	isolation		
Tremblay and Zaret, Dev Biol 2005
SI-Tayeb et al. Dev Cell 2010
Fiorotot et al. Acta 2018
Douarin Med Biol1975
Gualdi et al. Genes Dev 1996
Jung et al Science1999
Kamiya et al EMBO J 1999
Rossi et al; Genes Dev2001
Zaret et al Nat Rev Genet 2002
D’Amour Nat Biotechnol 2005
Han et al. Stem Cells 2011
Adapted	from	Prior	N,	Inacio	P	and	Huch	M	Gut	2019		
Activin/
Nodal
WNT
FGF
BMP
Hepatocytes
+
Cholangiocytes
Construction of liver organoids
Messina	A	et	al.	Cells	2022	
500 µm 200 µm 200 µm 200 µm
hiPSCs iDE (day 5) iHE (day 8) iHB (day 10)
3D
0
1
2
3
4
5
6
7
d13 d16 d18 d20 d25
µg*millioncells/24h
2D 3D AFP secretion
0
0,2
0,4
0,6
0,8
1
d13 d16 d18 d20 d25
µg
*millioncells/24h
3D 2D
ALB secretion
ActivinA
hiPSC BMP4
DE
•  FGF4
•  EGF
•  HGF
HE
•  HGF
•  OSM
•  Dex
HB
•  HGF
•  OSM
•  Dex
IH MH
1h 2 weeks
Phall
Nuclei
Confocal images of spheroid at day 25 of the differentiation protocol.
ALB HNF4α
Nuclei
200 µm
Self-assembling
3D configuration allows to generate hiPSC-derived liver
organoids with hepatic functions equivalent to PHHs
Bile acid secretion and bile canaliculi network
analysis of iHep-Orgs
Messina	A	et	al.	Cells	2022	
Bile acid production and secretion by iHep-
Orgs in culture supernatants at day 20
Live imaging of the bile canaliculi network
formed by excretion of the fluorescent probe DCFA
in iHep-Org at day 38
Immunofluorescence staining for the apical
Membrane transporter BSEP in iHep-Org
at day 38
Liver-on-chip	
HepaRG	
Boul	M	Sci	Reports	2021
Chip response to acetaminophen (APAP) exposure.
Cell viability in control and treated chips
(CTRL n = 3 chips, 2 mM APAP n = 2 chips)
Immunofluorescent images of
a control chip, a chip treated with APAP.
nuclei (blue), ZO-1 (green) and MDR3 (red)
Boul	M	Sci	Reports	2021
At high-dose, the common
signature of the three
treatments reflected liver
steatosis profile highlighted by
the modulation
of genes related to PPAR
signaling, fatty acid, lipid
metabolism and
steroid biosynthesis.
Metabolomic, profiled
showed high level of fatty acids
and lipids (decanoic,
tetradecanoic and
palmitic acids), glucose,
fructose and tagatose
Schematic of key components of the
enterohepatic bile acid synthesis and
recycling pathways.
HLOs respond physiologically when physically
coupled to bile acid-treated ileal HIOs
Transcriptional profiling of primary cholangiocytes
Sampaziotis F et al. Science 2021
Cholangiocyte Organoid identity is
controlled by niche stimuli
Sampaziotis F et al. Science 2021
Cholangiocyte organoids (COs) rescue cholangiopathy
following transplantation and assume an identity
corresponding to the site of engraftment.
Sampaziotis F et al. Science 2021
Transplantation of cholangiocyte
organoids in human
Up regulation of intrahepatic
(SOX4) And loss of gallbladder Sox17
and improvement of bile properties
Absence of RFP cells
in the perfusate
Sampaziotis F et al. Science 2021
RHU
A	building	block	approach	towards	a	fully	functional	liver
Differentiation
of
liver cells
from
human pluripotent
stem cells
and
applications
Alexis Bernatets
Alan J Rajendran
Ana Mesic
Bruno
Le Pioufle
Sakina
Bensallem
Microfluidics/
Liver On chip devices
Anne Dubart-Kupperschmitt
Nassima Benzoubir
Mano Boul
Marwa Hussein
Eleanor Luce
Antonietta Messina
« Toute imagination humaine
vient du coeur ».
Paracelse

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En Recherche Jean Charles Duclos Vallée.pdf

  • 1. Top 5 in Liver and bioengineering Jean-Charles Duclos-Vallée Centre Hépato-Biliaire Paul-Brousse Hospital
  • 2. Microtechnology and applications in liver bioengineering Microatterning Co-culture Encapsulation Bioartificial/ Transplantable bioengineered liver Drug screening Disease modelling
  • 3. Microtechnology and applications in liver bioengineering Micropatterning Co-culture Encapsulation Bioartificial/ Transplantable bioengineered liver Drug screening Disease modelling Microfluidics/ On chip devices Biomaterials Biomaterials 2D Cell culture
  • 4. Two main types of devices Artificial Bio Artificial Living component A Necessity ! Figaro S, Pereira U, …, Legallais C et al. Int J Organs 2017
  • 5. Global representation of the differentiation protocol of hiPSCs into hepatocytes and encapsulation into alginate beads CHIR, Activin A, LY FGF2, BMP4, FGF4, HGF Definitive endoderm (DE) hiPSCs Hepatoblasts (iHBs) Spheroid HGF, OSM, Dex, SB, CE, Vk iHBs spheroid encapsulation and hepatocyte differentiation Encapsulated spheroids (E-3D) Day 10-11 iHB self- aggregation iHBs differentiation Day 26 Day 20 Day 16 Day 11 500 µm 500 µm 500 µm 500 µm Encapsulation Day 10 500 µm Morphology of encapsulated spheroids From Marwa Hussein
  • 6.
  • 7. Distribution of PLL and elastic modulus of the surface PLL Permeability of empty beads (coated or not with PLL) to fluorescent markers (albumin, IgG, nanoparticles of different diameters)
  • 8. Distribution of PLL and elastic modulus of the surface PLL Permeability of empty beads (coated or not with PLL) to fluorescent markers (albumin, IgG, nanoparticles of different diameters) Metabolic activities of cells in alginate‐PLL beads, measured on Day 14, over 6 h' incubation in equivalent pathological plasma medium Ammonia detoxification rate Lactate detoxification rate Albumin production
  • 9.
  • 10. Towards a functional artificial liver From Université Technologique de Compiègne
  • 11.
  • 12. Definition of organoid: in vitro 3D cellular cluster derived from tissue- resident stem/progenitor cells, embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) that recapitulates the functionality of the tissue of origin Lancaster MA and Knoblich JA. Science 2014 Huch M and Koo BK. Development 2015
  • 13. Organogenesis and stages for organoid progenitor isolation Tremblay and Zaret, Dev Biol 2005 SI-Tayeb et al. Dev Cell 2010 Fiorotot et al. Acta 2018 Douarin Med Biol1975 Gualdi et al. Genes Dev 1996 Jung et al Science1999 Kamiya et al EMBO J 1999 Rossi et al; Genes Dev2001 Zaret et al Nat Rev Genet 2002 D’Amour Nat Biotechnol 2005 Han et al. Stem Cells 2011 Adapted from Prior N, Inacio P and Huch M Gut 2019 Activin/ Nodal WNT FGF BMP Hepatocytes + Cholangiocytes
  • 14. Construction of liver organoids Messina A et al. Cells 2022 500 µm 200 µm 200 µm 200 µm hiPSCs iDE (day 5) iHE (day 8) iHB (day 10) 3D 0 1 2 3 4 5 6 7 d13 d16 d18 d20 d25 µg*millioncells/24h 2D 3D AFP secretion 0 0,2 0,4 0,6 0,8 1 d13 d16 d18 d20 d25 µg *millioncells/24h 3D 2D ALB secretion ActivinA hiPSC BMP4 DE •  FGF4 •  EGF •  HGF HE •  HGF •  OSM •  Dex HB •  HGF •  OSM •  Dex IH MH 1h 2 weeks Phall Nuclei Confocal images of spheroid at day 25 of the differentiation protocol. ALB HNF4α Nuclei 200 µm Self-assembling 3D configuration allows to generate hiPSC-derived liver organoids with hepatic functions equivalent to PHHs
  • 15. Bile acid secretion and bile canaliculi network analysis of iHep-Orgs Messina A et al. Cells 2022 Bile acid production and secretion by iHep- Orgs in culture supernatants at day 20 Live imaging of the bile canaliculi network formed by excretion of the fluorescent probe DCFA in iHep-Org at day 38 Immunofluorescence staining for the apical Membrane transporter BSEP in iHep-Org at day 38
  • 16.
  • 18. Chip response to acetaminophen (APAP) exposure. Cell viability in control and treated chips (CTRL n = 3 chips, 2 mM APAP n = 2 chips) Immunofluorescent images of a control chip, a chip treated with APAP. nuclei (blue), ZO-1 (green) and MDR3 (red) Boul M Sci Reports 2021
  • 19.
  • 20.
  • 21.
  • 22. At high-dose, the common signature of the three treatments reflected liver steatosis profile highlighted by the modulation of genes related to PPAR signaling, fatty acid, lipid metabolism and steroid biosynthesis.
  • 23. Metabolomic, profiled showed high level of fatty acids and lipids (decanoic, tetradecanoic and palmitic acids), glucose, fructose and tagatose
  • 24.
  • 25. Schematic of key components of the enterohepatic bile acid synthesis and recycling pathways.
  • 26. HLOs respond physiologically when physically coupled to bile acid-treated ileal HIOs
  • 27.
  • 28. Transcriptional profiling of primary cholangiocytes Sampaziotis F et al. Science 2021
  • 29. Cholangiocyte Organoid identity is controlled by niche stimuli Sampaziotis F et al. Science 2021
  • 30. Cholangiocyte organoids (COs) rescue cholangiopathy following transplantation and assume an identity corresponding to the site of engraftment. Sampaziotis F et al. Science 2021
  • 31. Transplantation of cholangiocyte organoids in human Up regulation of intrahepatic (SOX4) And loss of gallbladder Sox17 and improvement of bile properties Absence of RFP cells in the perfusate Sampaziotis F et al. Science 2021
  • 33. Differentiation of liver cells from human pluripotent stem cells and applications Alexis Bernatets Alan J Rajendran Ana Mesic Bruno Le Pioufle Sakina Bensallem Microfluidics/ Liver On chip devices Anne Dubart-Kupperschmitt Nassima Benzoubir Mano Boul Marwa Hussein Eleanor Luce Antonietta Messina
  • 34. « Toute imagination humaine vient du coeur ». Paracelse