Scientists Transform Skin Cells into Functioning Liver Cells

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Scientists Transform Skin Cells into Functioning Liver Cells
. x2 ~! i3 w5 J) Q- F6 I2 w; SJoint Gladstone-UCSF study highlights novel reprogramming method; offers new hope for
$ L2 e8 t5 s" ]* Ctreating liver failure
+ i  O( H8 n+ F) m7 GEMBARGOED UNTIL 1PM ET, February 23, 2014$ o- j0 M( B' a) ^7 d
SAN FRANCISCO, CA—February 23, 2014—The power of regenerative medicine now allows
8 f0 x3 R" U( Z7 a, u. Escientists to transform skin cells into cells that closely resemble heart cells, pancreas cells and
6 |; Q7 K) T$ a  D) _; @( keven neurons. However, a method to generate cells that are fully mature—a crucial
- p. ~& p# k7 Nprerequisite for life-saving therapies—has proven far more difficult. But now, scientists at the  f! s8 G0 |# p
Gladstone Institutes and the University of California, San Francisco (UCSF), have made an3 M# {; C  P+ \& \
important breakthrough: they have discovered a way to transform skin cells into mature, fully) I' |% t+ F0 X4 P7 p$ d
functioning liver cells that flourish on their own, even after being transplanted into laboratory
" `* m' L1 T( e  p' Janimals modified to mimic liver failure.
! P& A* M. i+ _5 ~$ Z% V% W2 z: sIn previous studies on liver-cell reprogramming, scientists had difficulty getting stem cellderived
3 k* V$ p+ C: `* F8 ^" c/ nliver cells to survive once being transplanted into existing liver tissue. But the% @: {& k( u+ X7 Q* y8 o
Gladstone-UCSF team figured out a way to solve this problem. Writing in the latest issue of the3 I9 ]/ ~* ^  ~" k6 f+ h" B, ~$ L
journal Nature, researchers in the laboratories of Gladstone Senior Investigator Sheng Ding,
/ N8 |  Q+ h' T* O* o6 `+ BPhD, and UCSF Associate Professor Holger Willenbring, MD, PhD, reveal a new cellular
+ e1 v5 a' ~# ?- a; x8 R2 L$ Oreprogramming method that transforms human skin cells into liver cells that are virtually8 X% r: y( Q: A+ h& {6 b
indistinguishable from the cells that make up native liver tissue.
0 a) Y+ C  g3 E$ e( Y; tThese results offer new hope for the millions of people suffering from, or at risk of developing,* d1 G& g3 C# g! [$ ~5 d
liver failure—an increasingly common condition that results in progressive and irreversible loss
" V9 K1 ?0 @8 r) u; x6 @of liver function. At present, the only option is a costly liver transplant. So, scientists have long
& r' T: b% w! clooked to stem cell technology as a potential alternative. But thus far they have come up
$ g6 V2 q9 |- b  j2 Elargely empty-handed.0 T3 \3 [+ L/ W! T( ]
“Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order
$ }8 p. G& J  vto then grow liver cells,” explained Dr. Ding, one of the paper’s senior authors, who is also a* \0 }) l9 |0 w, l6 P; L0 P( ?
professor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. “However,
; i3 L9 j2 {( k3 Z% v) Egenerating these so-called induced pluripotent stem cells, or iPS cells, and then transforming
, L: _4 s! `! Vthem into liver cells wasn’t always resulting in complete transformation. So we thought that,
& b7 @" ^5 b4 _$ ?+ m/ g( g- p1 C! }rather than taking these skin cells all the way back to a pluripotent, stem cell-like state,
, |+ g% ^- N; J3 \- N& @perhaps we could take them to an intermediate phase.”
' e. _; d* k4 k- }/ x5 e5 r. cThis research, which was performed jointly at the Roddenberry Center for Stem Cell Research
5 b& ?% n0 L& `0 c1 qat Gladstone and the Broad Center of Regeneration Medicine and Stem Cell Research at
0 T$ p- f0 T3 g1 T( SUCSF, involved using a ‘cocktail’ of reprogramming genes and chemical compounds to# T* N& B4 }1 g
transform human skin cells into cells that resembled the endoderm. Endoderm cells are cells
2 Q& G- X7 }8 x6 ?5 k! f% e& zthat eventually mature into many of the body’s major organs—including the liver." O+ t. m3 g! t9 O
“Instead of taking the skin cells back to the beginning, we took them only part way, creating
% V$ W, \; m; n2 J8 A4 X8 Lendoderm-like cells,” added Gladstone and CIRM Postdoctoral Scholar Saiyong Zhu, PhD, one
! j' i; ]5 t: gof the paper’s lead authors. “This step allowed us to generate a large reservoir of cells that
! g. G/ D: l; F5 S3 Q3 H; [could more readily be coaxed into becoming liver cells.”
' z) |& c2 h+ L+ n# [0 q% A' V5 S* x9 kNext, the researchers discovered a set of genes and compounds that can transform these
& H- G2 {4 F3 ^: \cells into functioning liver cells. And after just a few weeks, the team began to notice a
. u4 z3 P# n6 htransformation.4 s, B+ q) M* Z0 j
“The cells began to take on the shape of liver cells, and even started to perform regular livercell
$ M* @$ R3 z/ sfunctions,” said UCSF Postdoctoral Scholar Milad Rezvani, MD, the paper’s other lead1 e5 J1 k; [; ^  x8 |
author. “They weren’t fully mature cells yet—but they were on their way.”  P0 G5 h9 k  S9 g( ~: M; n
Now that the team was encouraged by these initial results in a dish, they wanted to see what
5 D; q9 z& K8 T$ h; p4 Q' Awould happen in an actual liver. So, they transplanted these early-stage liver cells into the
3 Q% t" G, U1 L8 l/ D8 Z7 elivers of mice. Over a period of nine months, the team monitored cell function and growth by
* r) k8 A$ I1 A6 z0 ~% S. D+ ^( kmeasuring levels of liver-specific proteins and genes.& R  A, I9 q; q/ L( r, G. g# _
Two months post-transplantation, the team noticed a boost in human liver protein levels in the) L- s! C2 X* T* `; i7 V
mice, an indication that the transplanted cells were becoming mature, functional liver cells.. h7 y' c% V2 v/ D0 J) c# c; Y
Nine months later, cell growth had shown no signs of slowing down. These results indicate that
2 w8 n$ g8 p3 m5 |the researchers have found the factors required to successfully regenerate liver tissue.0 x( B- C8 h- m
“Many questions remain, but the fact that these cells can fully mature and grow for months6 E! a- v( N- G
post-transplantation is extremely promising,” added Dr. Willenbring, associate director of the; E/ I  z7 t' P( v: x2 S
UCSF Liver Center and the paper’s other senior author. “In the future, our technique could- `* \% z0 U, b. V
serve as an alternative for liver-failure patients who don’t require full-organ replacement, or/ l& u5 m2 a( k9 G; o" a% G: ]: Q
who don’t have access to a transplant due to limited donor organ availability.”# E) J* ]1 e3 z2 T
Other scientists who participated in this research include UCSF researchers Jack Harbell, MD,5 \" Z, d* z* e; c$ [$ g
also a lead author on the paper, as well as Aras Mattis, MD, PhD, Alan Wolfe and Leslie Benet,
3 x- L5 {+ f6 h5 y0 }$ XPhD. Funding was provided by the following: the California Institute for Regenerative Medicine,; z1 d* G% v9 Z% {# G2 a5 X
the National Institutes of Health, the German Academic Exchange Service, and the Society of) B8 F1 y; e4 R
University Surgeons.
+ R2 F" J1 a' ]( O, A5 NAbout the Gladstone Institutes. G; m. ~  d  Z( s$ o' M9 Q
Gladstone is an independent and nonprofit biomedical-research organization dedicated to# f( Z5 O% Q8 o( n
accelerating the pace of scientific discovery and innovation to prevent, treat and cure
3 ~8 r0 Q7 E4 [cardiovascular, viral and neurological diseases. Gladstone is affiliated with the University of$ o0 e/ f; Z* _! F# \1 p
California, San Francisco.4 w2 E7 `: g( j
About UCSF1 T! G1 k" @0 c
UCSF is a leading university dedicated to promoting health worldwide through advanced# T) k: I6 D# x  t; M, G
biomedical research, graduate-level education in the life sciences and health professions, and
/ u, K1 ], [0 n! _1 e: rexcellence in patient care. It includes top-ranked graduate schools of dentistry, medicine,
# P2 e1 ?5 Z7 Y2 t  xnursing and pharmacy, a graduate division with nationally renowned programs in basic
# O% e. {" a7 v" {6 H) ubiomedical, translational and population sciences, as well as a preeminent biomedical" @" s" l: P, j7 ~+ Q9 z
research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff  {! Z, W$ Z/ S
Children’s Hospital.! \! ]% D1 F( V3 K, q
Press Contacts0 T& g# ?" _5 x- O
Anne Holden
4 C2 L2 _+ S, j8 ^Gladstone Institutes
5 S! e5 N/ P( \  g: \5 u415.734.2534
8 l( q# |. h: y+ fanne.holden@gladstone.ucsf.edu3 e; q4 b& q; _( j5 ]1 W2 D8 P
Jeff Norris9 S0 x9 x- y  j+ V/ q2 Z' ~) C
UCSF- M. z; J" s3 y" g- f
415.476.82559 \, f, }3 b! u% ^! u1 X
JNorris@pubaff.ucsf.edu