Scientists Transform Skin Cells into Functioning Liver Cells

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Scientists Transform Skin Cells into Functioning Liver Cells
; r/ O' H1 w& |; ?+ N2 p6 u4 q$ XJoint Gladstone-UCSF study highlights novel reprogramming method; offers new hope for
1 o- m6 S! @  r  E% n! @7 Qtreating liver failure
* N8 ?: T% o7 x& N; LEMBARGOED UNTIL 1PM ET, February 23, 2014
4 K2 v4 }' y+ Q' Y4 ~5 b9 USAN FRANCISCO, CA—February 23, 2014—The power of regenerative medicine now allows( r9 ~: L! u  M- r  E! V' j
scientists to transform skin cells into cells that closely resemble heart cells, pancreas cells and
1 s/ U9 L1 z) S, c6 y; t- B; O# ]even neurons. However, a method to generate cells that are fully mature—a crucial
% C8 @4 Z) ?7 l- |prerequisite for life-saving therapies—has proven far more difficult. But now, scientists at the' h6 e6 Z" {) x% a. t% y, F
Gladstone Institutes and the University of California, San Francisco (UCSF), have made an' U3 J) ], L! m- {$ V+ v3 F: C
important breakthrough: they have discovered a way to transform skin cells into mature, fully/ t- z3 m1 I) q1 E7 y% p
functioning liver cells that flourish on their own, even after being transplanted into laboratory
, d; q/ k: _& W' Nanimals modified to mimic liver failure.
$ b  j" K  z& J2 a8 p5 pIn previous studies on liver-cell reprogramming, scientists had difficulty getting stem cellderived  u% N: M4 O; N& S2 v
liver cells to survive once being transplanted into existing liver tissue. But the
' `+ v$ ~  d! E9 H1 x) hGladstone-UCSF team figured out a way to solve this problem. Writing in the latest issue of the
) h9 a2 d4 R! Bjournal Nature, researchers in the laboratories of Gladstone Senior Investigator Sheng Ding,2 n+ I3 C/ Q" ~8 R$ C% C# p
PhD, and UCSF Associate Professor Holger Willenbring, MD, PhD, reveal a new cellular
- F; `# r5 n3 @5 |" r, lreprogramming method that transforms human skin cells into liver cells that are virtually- c8 I6 ?& I% w* P: M3 O) R
indistinguishable from the cells that make up native liver tissue.
2 _: R' N; r$ `+ K, R* ~# v9 TThese results offer new hope for the millions of people suffering from, or at risk of developing,
) d  @. s) w2 I+ c' B2 _+ Fliver failure—an increasingly common condition that results in progressive and irreversible loss
0 D1 u  |8 F, Q& S* fof liver function. At present, the only option is a costly liver transplant. So, scientists have long
3 J/ T" ^+ ]( a" _looked to stem cell technology as a potential alternative. But thus far they have come up
+ v  |* m3 J$ ?8 z( ulargely empty-handed.
: b& o4 ^2 W1 x' L9 ]“Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order: }0 w7 I+ b' H# p4 n
to then grow liver cells,” explained Dr. Ding, one of the paper’s senior authors, who is also a! T: a$ K0 T7 M0 R5 x# |  d9 s
professor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. “However,
% b; m: `( H7 D1 Bgenerating these so-called induced pluripotent stem cells, or iPS cells, and then transforming" w6 h, ~- V& q( x4 e) P* l- M
them into liver cells wasn’t always resulting in complete transformation. So we thought that,* s: f+ I. K' {. V+ y
rather than taking these skin cells all the way back to a pluripotent, stem cell-like state,
; H5 F3 d% A' a/ y0 Tperhaps we could take them to an intermediate phase.”" ^  G6 A0 T& o5 R* Z1 `" B
This research, which was performed jointly at the Roddenberry Center for Stem Cell Research: U% y$ F2 P. N" B
at Gladstone and the Broad Center of Regeneration Medicine and Stem Cell Research at+ f9 J8 L# ?' [- \
UCSF, involved using a ‘cocktail’ of reprogramming genes and chemical compounds to
( b7 O' \* k8 k* C) z, R7 S/ S# a6 w1 btransform human skin cells into cells that resembled the endoderm. Endoderm cells are cells; c: _& z5 E8 ?+ C) w& M
that eventually mature into many of the body’s major organs—including the liver.
  X3 e  Z! f9 Y- K3 V“Instead of taking the skin cells back to the beginning, we took them only part way, creating0 n5 j7 D1 J! q$ h( u3 c
endoderm-like cells,” added Gladstone and CIRM Postdoctoral Scholar Saiyong Zhu, PhD, one7 ^2 b% N6 e6 Q7 |1 g# _- g
of the paper’s lead authors. “This step allowed us to generate a large reservoir of cells that' C1 T; s  O% T8 z! V0 C' X
could more readily be coaxed into becoming liver cells.”
0 i$ h* Z  W, g8 FNext, the researchers discovered a set of genes and compounds that can transform these  S" E" z6 J) J
cells into functioning liver cells. And after just a few weeks, the team began to notice a
8 O4 c9 w( z% j) w; x! _3 Ntransformation.
! S. ^6 m* x' p2 {“The cells began to take on the shape of liver cells, and even started to perform regular livercell
9 {! U& F  Z! `+ B. }functions,” said UCSF Postdoctoral Scholar Milad Rezvani, MD, the paper’s other lead9 T% L+ V, G1 a! v
author. “They weren’t fully mature cells yet—but they were on their way.”
& E! p1 p9 _$ I+ j: X3 vNow that the team was encouraged by these initial results in a dish, they wanted to see what
+ V* J0 [6 `& \0 x. x! o* ^; u$ ^* Nwould happen in an actual liver. So, they transplanted these early-stage liver cells into the
6 n6 ~% u5 e2 I$ [( c& ylivers of mice. Over a period of nine months, the team monitored cell function and growth by
! {% f4 H0 z0 G6 ^  Emeasuring levels of liver-specific proteins and genes.' ]3 d2 @9 E$ D
Two months post-transplantation, the team noticed a boost in human liver protein levels in the9 b& }+ g$ x2 [2 X2 p
mice, an indication that the transplanted cells were becoming mature, functional liver cells.
$ }6 M; s% U7 j5 G3 v, ONine months later, cell growth had shown no signs of slowing down. These results indicate that$ }4 P4 R3 X5 Q5 D) `
the researchers have found the factors required to successfully regenerate liver tissue.1 _; V- n: ~9 j2 E$ B
“Many questions remain, but the fact that these cells can fully mature and grow for months( ^+ D. N+ H( M; t6 {4 o
post-transplantation is extremely promising,” added Dr. Willenbring, associate director of the
7 V- J5 O, j- WUCSF Liver Center and the paper’s other senior author. “In the future, our technique could  b$ h) {# ]0 s# i/ X
serve as an alternative for liver-failure patients who don’t require full-organ replacement, or* V* i9 }6 p; t6 P8 O
who don’t have access to a transplant due to limited donor organ availability.”
# I7 n2 N, A* _$ F9 kOther scientists who participated in this research include UCSF researchers Jack Harbell, MD,/ a4 R+ @; q1 G& q
also a lead author on the paper, as well as Aras Mattis, MD, PhD, Alan Wolfe and Leslie Benet,
- |& K$ }) d& F" MPhD. Funding was provided by the following: the California Institute for Regenerative Medicine,
' U( f6 s# x, ythe National Institutes of Health, the German Academic Exchange Service, and the Society of# X' u% v9 ]. V$ v) H
University Surgeons.6 M( {" @6 y! R2 f
About the Gladstone Institutes% [3 ?" h4 P  O+ P. z
Gladstone is an independent and nonprofit biomedical-research organization dedicated to
5 Y5 m( U' e; I( oaccelerating the pace of scientific discovery and innovation to prevent, treat and cure
; z7 h* H8 r+ C! S* E( qcardiovascular, viral and neurological diseases. Gladstone is affiliated with the University of
# h& u) y6 ?; Q, Q$ I% H+ NCalifornia, San Francisco.. B9 x6 n* b7 I) K5 N7 ]
About UCSF
. W: h% U; i+ ]+ n- FUCSF is a leading university dedicated to promoting health worldwide through advanced
9 r8 w! {) Z9 ^biomedical research, graduate-level education in the life sciences and health professions, and. i4 P! y0 E. H0 b. X  u+ c" y  T
excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine,9 i; r* |8 p/ ^5 B, i1 B- J1 L& l
nursing and pharmacy, a graduate division with nationally renowned programs in basic
0 _! M) M, ?# }# z. k, rbiomedical, translational and population sciences, as well as a preeminent biomedical/ p1 I, [+ L  Q1 |1 ?$ b# Z
research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff- J# d. E. q, g) S9 Y
Children’s Hospital.
9 Z7 t8 j, F  a+ P" pPress Contacts% }0 r0 c% X) [* E
Anne Holden
* I$ R. b) U6 h5 ?1 c) WGladstone Institutes
  H& j* f/ X9 }: p. t/ `415.734.25346 o* k( r; d7 i/ a- e5 F. F# [
anne.holden@gladstone.ucsf.edu
7 p" j& g) Q- U6 RJeff Norris+ ]+ T& ~6 Z- A0 R. Q* s1 G
UCSF
3 N0 `% c2 N- U7 b0 D; p415.476.8255
9 O* \. g9 S, s$ tJNorris@pubaff.ucsf.edu