Scientists Transform Skin Cells into Functioning Liver Cells

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Scientists Transform Skin Cells into Functioning Liver Cells
% Y( d% q' ?' i  u) |3 `' X2 G$ EJoint Gladstone-UCSF study highlights novel reprogramming method; offers new hope for, [3 p/ L2 _, \5 c  q! ]
treating liver failure2 T8 d$ o. K5 c7 f& m6 y* E
EMBARGOED UNTIL 1PM ET, February 23, 20145 p$ {% h7 s+ V! R: m
SAN FRANCISCO, CA—February 23, 2014—The power of regenerative medicine now allows
" ]# V6 `3 @0 w- Q6 o6 }2 dscientists to transform skin cells into cells that closely resemble heart cells, pancreas cells and4 l% j- Q5 u7 t' _9 o
even neurons. However, a method to generate cells that are fully mature—a crucial% Z1 v9 m5 T( K6 U9 t& o
prerequisite for life-saving therapies—has proven far more difficult. But now, scientists at the
* K! v- l1 @9 u' q5 `, n# f1 mGladstone Institutes and the University of California, San Francisco (UCSF), have made an2 r! f6 V0 b: o/ b. X; i3 ~
important breakthrough: they have discovered a way to transform skin cells into mature, fully& W' k. x$ N$ }# o
functioning liver cells that flourish on their own, even after being transplanted into laboratory
- v0 ?9 D( |* ?* @7 y# e8 ]animals modified to mimic liver failure.1 m- x4 Z! z- f7 `
In previous studies on liver-cell reprogramming, scientists had difficulty getting stem cellderived- L( H& r% c0 I! s" k
liver cells to survive once being transplanted into existing liver tissue. But the3 m8 M: W7 y) ~
Gladstone-UCSF team figured out a way to solve this problem. Writing in the latest issue of the
) A5 g0 c1 X: T4 I5 S4 a4 B+ Zjournal Nature, researchers in the laboratories of Gladstone Senior Investigator Sheng Ding,4 {. m8 e; @' w" l( h
PhD, and UCSF Associate Professor Holger Willenbring, MD, PhD, reveal a new cellular
2 d9 ^7 a$ J3 F$ }4 |7 z& J7 q# Nreprogramming method that transforms human skin cells into liver cells that are virtually, H: T$ F/ B. \4 b: j  L! l1 _/ |
indistinguishable from the cells that make up native liver tissue.
/ r* ?) I6 Q3 e" n- SThese results offer new hope for the millions of people suffering from, or at risk of developing,
9 J6 T7 C/ o0 l" a: F, hliver failure—an increasingly common condition that results in progressive and irreversible loss0 l9 e7 y+ g( k0 [) k! Z/ }
of liver function. At present, the only option is a costly liver transplant. So, scientists have long
3 _( n6 N9 A+ h- }; O. olooked to stem cell technology as a potential alternative. But thus far they have come up% o0 `$ B& ?% ^! k8 Y
largely empty-handed.
/ s) g, s/ m  j2 J, @) c- Q“Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order( m- w, a1 J& f' x' Y: _& k5 V0 A
to then grow liver cells,” explained Dr. Ding, one of the paper’s senior authors, who is also a' f* ^% x7 U2 v. M6 D9 P6 u& g5 G
professor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. “However,
; Y( O+ p8 \/ ?. W4 `4 wgenerating these so-called induced pluripotent stem cells, or iPS cells, and then transforming% o; f0 h$ e( L
them into liver cells wasn’t always resulting in complete transformation. So we thought that,
0 L# d0 v9 E& D. h' G$ hrather than taking these skin cells all the way back to a pluripotent, stem cell-like state,
0 ^+ G$ x# K. rperhaps we could take them to an intermediate phase.”
/ r2 I: b) G  @& u4 n6 yThis research, which was performed jointly at the Roddenberry Center for Stem Cell Research. u$ i" ?" B$ i6 K
at Gladstone and the Broad Center of Regeneration Medicine and Stem Cell Research at1 ~1 t* W- n- H- \" X/ o* V  \) V* _
UCSF, involved using a ‘cocktail’ of reprogramming genes and chemical compounds to9 i  h6 y, I. D
transform human skin cells into cells that resembled the endoderm. Endoderm cells are cells
% f( P" i+ z7 Kthat eventually mature into many of the body’s major organs—including the liver.. K- m, _9 B! `+ l) k7 O. d
“Instead of taking the skin cells back to the beginning, we took them only part way, creating
; V# j" e) A( i% |; Wendoderm-like cells,” added Gladstone and CIRM Postdoctoral Scholar Saiyong Zhu, PhD, one
/ T! ?; \( e% A( G/ Kof the paper’s lead authors. “This step allowed us to generate a large reservoir of cells that' P, y, Z4 @& O2 @. D! k
could more readily be coaxed into becoming liver cells.”* p/ Z) L+ O' Q
Next, the researchers discovered a set of genes and compounds that can transform these
4 ]0 C+ x. R: \7 zcells into functioning liver cells. And after just a few weeks, the team began to notice a) |# a3 @* \5 W5 }
transformation.7 j$ F& S  E1 b, n, f
“The cells began to take on the shape of liver cells, and even started to perform regular livercell
) y6 ~9 e+ c5 |+ B% N0 bfunctions,” said UCSF Postdoctoral Scholar Milad Rezvani, MD, the paper’s other lead4 N4 P9 c$ }# \1 ^: b# e& C4 H
author. “They weren’t fully mature cells yet—but they were on their way.”
" @$ k0 J( M; L! E0 ~; FNow that the team was encouraged by these initial results in a dish, they wanted to see what$ |6 C# @0 J1 ]7 v6 |' ]2 q1 n
would happen in an actual liver. So, they transplanted these early-stage liver cells into the, g" f0 z* ~" ?  `$ g6 s
livers of mice. Over a period of nine months, the team monitored cell function and growth by3 Y* k7 ?+ T4 G+ `7 {: v# ?
measuring levels of liver-specific proteins and genes.+ u" k  S+ E; n2 m. D) L/ A, H0 k0 u
Two months post-transplantation, the team noticed a boost in human liver protein levels in the% H5 t6 V4 l* |, ^3 O0 x, d! D4 B
mice, an indication that the transplanted cells were becoming mature, functional liver cells.
+ n3 e* i. W; eNine months later, cell growth had shown no signs of slowing down. These results indicate that6 G2 \3 L# U! I' a3 G& N
the researchers have found the factors required to successfully regenerate liver tissue.
8 s" t4 s1 \8 Q# E“Many questions remain, but the fact that these cells can fully mature and grow for months+ D3 t6 W* C' k0 m, z% Z: [
post-transplantation is extremely promising,” added Dr. Willenbring, associate director of the
% {: W7 w+ f0 P& H$ l' TUCSF Liver Center and the paper’s other senior author. “In the future, our technique could
5 g" b2 z0 x  J, A1 N. D9 wserve as an alternative for liver-failure patients who don’t require full-organ replacement, or
( ^$ l+ `+ z3 Nwho don’t have access to a transplant due to limited donor organ availability.”0 y' @( T* l/ f- o9 Z
Other scientists who participated in this research include UCSF researchers Jack Harbell, MD,
. z( t9 o6 }( Q& ~, palso a lead author on the paper, as well as Aras Mattis, MD, PhD, Alan Wolfe and Leslie Benet,8 l+ W' \* i4 X% k
PhD. Funding was provided by the following: the California Institute for Regenerative Medicine,+ K' s& w+ X' p) ]* |; `
the National Institutes of Health, the German Academic Exchange Service, and the Society of% }% z) g9 u( h, x! o" s7 O" r
University Surgeons.% Y# Y2 A5 p7 P6 E/ k: U* u
About the Gladstone Institutes
, h+ ~! x& r  I$ CGladstone is an independent and nonprofit biomedical-research organization dedicated to0 ~; g7 w/ {; t1 a* x
accelerating the pace of scientific discovery and innovation to prevent, treat and cure$ P4 m1 t: C2 h9 l# k
cardiovascular, viral and neurological diseases. Gladstone is affiliated with the University of
5 ]1 k0 f' q9 `3 xCalifornia, San Francisco.4 K) u& q0 f$ P7 _. z6 P
About UCSF& m0 s# f0 M/ M" x6 W$ J
UCSF is a leading university dedicated to promoting health worldwide through advanced
0 [$ `: V6 M1 ]& Jbiomedical research, graduate-level education in the life sciences and health professions, and* H# Y) y( r5 @) ?" P8 \4 L+ k& P6 K
excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine,! J+ Q0 j. \% z0 u/ N0 e  E
nursing and pharmacy, a graduate division with nationally renowned programs in basic% Z8 }  k; `; G% W
biomedical, translational and population sciences, as well as a preeminent biomedical
) x# p; E# O/ F; hresearch enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff. f3 D* ^2 m) b8 h5 F7 Z4 s
Children’s Hospital.
8 K: k( k8 E2 Y% }; EPress Contacts
' v) K" o3 A' M. DAnne Holden* [/ t7 _9 _; h+ R. O# p
Gladstone Institutes. ^- G! N3 y: J& V# s' ^5 i
415.734.25343 R- T  v$ B4 S2 q: L; i! W
anne.holden@gladstone.ucsf.edu' [7 U6 u1 G  }& J  A, ^
Jeff Norris
# N7 D4 W' i: ]9 c/ RUCSF: K: P' X" V4 B  _% {
415.476.8255
& n4 z: y3 D0 M5 _: YJNorris@pubaff.ucsf.edu