Scientists Transform Skin Cells into Functioning Liver Cells

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Scientists Transform Skin Cells into Functioning Liver Cells- J- ?8 u8 z1 P
Joint Gladstone-UCSF study highlights novel reprogramming method; offers new hope for
# u: J  U$ ]6 L; Ntreating liver failure
& \3 Z2 Y) D* e4 IEMBARGOED UNTIL 1PM ET, February 23, 2014. U6 C- N7 r  \5 B' ^' P
SAN FRANCISCO, CA—February 23, 2014—The power of regenerative medicine now allows) o7 H; C  w4 }3 E
scientists to transform skin cells into cells that closely resemble heart cells, pancreas cells and
7 `! `3 J" h: S% x: y) f" Aeven neurons. However, a method to generate cells that are fully mature—a crucial
4 n% `. ?0 `6 bprerequisite for life-saving therapies—has proven far more difficult. But now, scientists at the
4 G' n: n2 v" ]  K$ Q3 BGladstone Institutes and the University of California, San Francisco (UCSF), have made an# P& g! B5 F) [3 n1 V6 q. S
important breakthrough: they have discovered a way to transform skin cells into mature, fully% h/ w; k# ~& {$ Z" n2 S' ?
functioning liver cells that flourish on their own, even after being transplanted into laboratory+ o  W2 n( v" ~5 O% U- J7 V+ ?
animals modified to mimic liver failure.
  J& t3 `( X* r$ XIn previous studies on liver-cell reprogramming, scientists had difficulty getting stem cellderived
1 D* R: B8 _; e  S% jliver cells to survive once being transplanted into existing liver tissue. But the
+ p) [9 `: O3 U. Z1 L; H; `Gladstone-UCSF team figured out a way to solve this problem. Writing in the latest issue of the
: _6 K: m( N6 R- R7 Ejournal Nature, researchers in the laboratories of Gladstone Senior Investigator Sheng Ding,
4 h9 T- F. c* {4 Z4 ~) e4 bPhD, and UCSF Associate Professor Holger Willenbring, MD, PhD, reveal a new cellular  ]& T/ a, a: p- L" W
reprogramming method that transforms human skin cells into liver cells that are virtually
) b, c' \6 o% @. j5 o0 Y+ Iindistinguishable from the cells that make up native liver tissue." K, H4 ~8 w1 B( ?2 D' {
These results offer new hope for the millions of people suffering from, or at risk of developing,
6 w7 F. e3 \& N: o7 b  T: z, e6 z3 Wliver failure—an increasingly common condition that results in progressive and irreversible loss
. R. ?; }2 B2 X: b8 q( vof liver function. At present, the only option is a costly liver transplant. So, scientists have long
2 U* B- M. o, ^6 d/ jlooked to stem cell technology as a potential alternative. But thus far they have come up
9 p- E! m" z( Flargely empty-handed.
) u3 J! M3 ]7 D1 ]“Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order: u. G; ~5 ]7 t1 p
to then grow liver cells,” explained Dr. Ding, one of the paper’s senior authors, who is also a
8 L4 U7 q- X0 a6 Q  nprofessor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. “However,
1 C5 c- v0 I  Vgenerating these so-called induced pluripotent stem cells, or iPS cells, and then transforming& d+ M: v6 w  A/ i2 p) v* S
them into liver cells wasn’t always resulting in complete transformation. So we thought that,
: d% k# P6 c; d$ d( H+ K6 ^: hrather than taking these skin cells all the way back to a pluripotent, stem cell-like state,
9 Q  O2 G4 b& y$ K# operhaps we could take them to an intermediate phase.”
5 X/ z" t' h' f: |This research, which was performed jointly at the Roddenberry Center for Stem Cell Research6 E: B+ d6 M' u3 w1 S0 r! l
at Gladstone and the Broad Center of Regeneration Medicine and Stem Cell Research at% ^  ?! P  ~! s/ ]
UCSF, involved using a ‘cocktail’ of reprogramming genes and chemical compounds to$ ?6 _/ Y, Q5 k( v- O! p
transform human skin cells into cells that resembled the endoderm. Endoderm cells are cells6 e. u0 A" u6 r! F1 j/ s% l( H
that eventually mature into many of the body’s major organs—including the liver.' }! t/ r: G# x" Y
“Instead of taking the skin cells back to the beginning, we took them only part way, creating. j: P5 c; J) x8 \
endoderm-like cells,” added Gladstone and CIRM Postdoctoral Scholar Saiyong Zhu, PhD, one* @3 Y( n$ N5 P9 B
of the paper’s lead authors. “This step allowed us to generate a large reservoir of cells that1 U; k3 g8 W4 K  G0 B: l1 Q
could more readily be coaxed into becoming liver cells.”2 ^" f; e6 ^6 I$ B9 a+ S" R
Next, the researchers discovered a set of genes and compounds that can transform these
: ]/ v8 s, f  L3 r/ Vcells into functioning liver cells. And after just a few weeks, the team began to notice a
: W  v& p& @7 U+ L" }transformation.
! l' F% z, J- g; w0 v6 c“The cells began to take on the shape of liver cells, and even started to perform regular livercell  Z  `0 U& U) |$ C3 s- u
functions,” said UCSF Postdoctoral Scholar Milad Rezvani, MD, the paper’s other lead4 _% s% s* Y6 w4 b
author. “They weren’t fully mature cells yet—but they were on their way.”; j1 h7 o% S8 A/ _$ \  C8 Z
Now that the team was encouraged by these initial results in a dish, they wanted to see what) @7 ]7 p) r: n
would happen in an actual liver. So, they transplanted these early-stage liver cells into the
' ]: U( T; E  {4 v8 U( ^livers of mice. Over a period of nine months, the team monitored cell function and growth by% \4 w8 p2 ^5 l5 ^6 s) m
measuring levels of liver-specific proteins and genes.
1 b9 K) {) L: z+ yTwo months post-transplantation, the team noticed a boost in human liver protein levels in the3 ?1 V- c, T  O
mice, an indication that the transplanted cells were becoming mature, functional liver cells.. \1 [# |6 L, l8 }/ }: ]1 S7 G9 R
Nine months later, cell growth had shown no signs of slowing down. These results indicate that" r# ~8 k1 O; O* z& w+ j6 K6 u
the researchers have found the factors required to successfully regenerate liver tissue.
7 m% ?7 n2 v& l) `$ e7 o“Many questions remain, but the fact that these cells can fully mature and grow for months
8 f% i( S& o$ O! _" Wpost-transplantation is extremely promising,” added Dr. Willenbring, associate director of the
& @2 T% C- r" A& C, v4 ]9 o# a8 w: eUCSF Liver Center and the paper’s other senior author. “In the future, our technique could
0 k: s8 A! H8 B" Cserve as an alternative for liver-failure patients who don’t require full-organ replacement, or
1 D: q/ ^9 t1 L' d$ h+ U! M8 L% R6 swho don’t have access to a transplant due to limited donor organ availability.”
/ t% K: c2 N& l3 L# |) i! u  [. rOther scientists who participated in this research include UCSF researchers Jack Harbell, MD,7 U9 U; D: F5 e% t6 e' z* u
also a lead author on the paper, as well as Aras Mattis, MD, PhD, Alan Wolfe and Leslie Benet,/ s5 X: ]( \1 }( t4 R  {: i5 e
PhD. Funding was provided by the following: the California Institute for Regenerative Medicine,
) B( y. x6 X! d+ _1 v9 _, zthe National Institutes of Health, the German Academic Exchange Service, and the Society of$ W  {' o5 M- ^
University Surgeons.
0 O4 y; g7 a# k. h8 ^( \About the Gladstone Institutes
% ^1 l( F* K. d! g) o1 K, B7 CGladstone is an independent and nonprofit biomedical-research organization dedicated to
; A# u) |% H" S! I) j( G2 E  [accelerating the pace of scientific discovery and innovation to prevent, treat and cure  g' [; i; l3 I+ V- ]0 [
cardiovascular, viral and neurological diseases. Gladstone is affiliated with the University of
; k& f) Q# V0 \California, San Francisco.4 y' n; B3 [8 o
About UCSF
5 l! @0 R$ D3 m* d5 F3 pUCSF is a leading university dedicated to promoting health worldwide through advanced$ |! f) L  o+ m+ O1 K1 S5 T
biomedical research, graduate-level education in the life sciences and health professions, and
) n; o* N& X% h9 pexcellence in patient care. It includes top-ranked graduate schools of dentistry, medicine,4 D- \" I+ L- r5 V* D9 Y, X
nursing and pharmacy, a graduate division with nationally renowned programs in basic
) e9 N  \3 s/ }* {biomedical, translational and population sciences, as well as a preeminent biomedical
4 E! j& E+ [- F3 y! Qresearch enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff1 f6 F: ~* h0 b3 Q
Children’s Hospital.: {" @& C' x/ n, x4 S+ X# |
Press Contacts1 l/ c+ O2 i( [4 k
Anne Holden
  y% A# p$ ?* T3 `$ P7 g: wGladstone Institutes: q' T# D6 }8 w0 j9 Y+ s1 O
415.734.2534% g2 r9 q. I; l* k
anne.holden@gladstone.ucsf.edu
+ B3 b) z3 k2 G% @8 W% fJeff Norris
( [8 Q9 r& H/ j6 p, X5 q: z' VUCSF: S' O$ M/ M, t7 M4 V  J- k0 U, J6 _
415.476.8255* W: T; r" D: E
JNorris@pubaff.ucsf.edu