Scientists Transform Skin Cells into Functioning Liver Cells

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Scientists Transform Skin Cells into Functioning Liver Cells7 @- X& f6 s% O! \
Joint Gladstone-UCSF study highlights novel reprogramming method; offers new hope for3 u! y$ D9 G! [% v8 C( r) X0 s
treating liver failure2 E/ }" X+ E- V# w
EMBARGOED UNTIL 1PM ET, February 23, 2014
8 U9 [; m; ?1 w7 USAN FRANCISCO, CA—February 23, 2014—The power of regenerative medicine now allows
) {' M( k% }7 R/ s5 t7 w! D1 Dscientists to transform skin cells into cells that closely resemble heart cells, pancreas cells and9 X, V) Q* V" k% H( j
even neurons. However, a method to generate cells that are fully mature—a crucial
7 E  x3 B( L2 G0 a0 Cprerequisite for life-saving therapies—has proven far more difficult. But now, scientists at the3 W( O8 k7 e3 Q
Gladstone Institutes and the University of California, San Francisco (UCSF), have made an
) v% x, H2 Q4 {% ]important breakthrough: they have discovered a way to transform skin cells into mature, fully# e6 S2 Y1 P: }
functioning liver cells that flourish on their own, even after being transplanted into laboratory
" {$ {; x7 }' lanimals modified to mimic liver failure.* E. J" H  O% A- a
In previous studies on liver-cell reprogramming, scientists had difficulty getting stem cellderived
3 f/ I- e9 N( h& k- ]0 N* F6 tliver cells to survive once being transplanted into existing liver tissue. But the6 k  X+ E6 i& T, o5 ~6 V1 `
Gladstone-UCSF team figured out a way to solve this problem. Writing in the latest issue of the! [4 Y5 v- V5 P* t8 [( {
journal Nature, researchers in the laboratories of Gladstone Senior Investigator Sheng Ding,
0 C. a: M# a1 l- v2 A% Y0 V8 V& LPhD, and UCSF Associate Professor Holger Willenbring, MD, PhD, reveal a new cellular
/ v% g( w' A: R* e. J6 F- t1 E* U2 ireprogramming method that transforms human skin cells into liver cells that are virtually! C4 e( Q( ]3 i9 P( t
indistinguishable from the cells that make up native liver tissue.- N8 y4 B8 q1 V4 p
These results offer new hope for the millions of people suffering from, or at risk of developing,$ D: ^3 R7 X5 g7 E% D  ~
liver failure—an increasingly common condition that results in progressive and irreversible loss7 k3 R" W: Y! U" f2 U8 M8 R7 v* G
of liver function. At present, the only option is a costly liver transplant. So, scientists have long
( J% v, h- m, mlooked to stem cell technology as a potential alternative. But thus far they have come up
* N/ n9 v" u& a! xlargely empty-handed.
9 ~$ C/ Y" [" K: R( z- T# @% }“Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order/ i8 O* N) @* i: B: P
to then grow liver cells,” explained Dr. Ding, one of the paper’s senior authors, who is also a
! Z/ h2 z0 p7 D% S4 l% d- J7 Wprofessor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. “However,
6 }, V" u6 N  }9 \$ h# w1 r  {6 sgenerating these so-called induced pluripotent stem cells, or iPS cells, and then transforming
; g3 j% g( q' \8 d( H* z* P4 \8 }them into liver cells wasn’t always resulting in complete transformation. So we thought that,  Y' V. Q: s; F2 M/ {
rather than taking these skin cells all the way back to a pluripotent, stem cell-like state,8 J& N' X5 W' F/ k1 N7 C7 @% v
perhaps we could take them to an intermediate phase.”. b% l0 w5 G3 m( h+ C5 J5 d
This research, which was performed jointly at the Roddenberry Center for Stem Cell Research
# T; z( @/ T1 N; \& Kat Gladstone and the Broad Center of Regeneration Medicine and Stem Cell Research at: R5 ^4 Z( @+ ~7 g! z" r# w
UCSF, involved using a ‘cocktail’ of reprogramming genes and chemical compounds to
$ u# n) {( v6 w8 }transform human skin cells into cells that resembled the endoderm. Endoderm cells are cells
  D6 q0 `1 O3 A3 dthat eventually mature into many of the body’s major organs—including the liver.: `, J  x5 j8 \* G7 W0 A
“Instead of taking the skin cells back to the beginning, we took them only part way, creating
% X, w% U7 y6 L5 [7 o* T5 cendoderm-like cells,” added Gladstone and CIRM Postdoctoral Scholar Saiyong Zhu, PhD, one
6 ~+ G8 h# P* Fof the paper’s lead authors. “This step allowed us to generate a large reservoir of cells that! v0 G3 u2 ?( d, \3 s& `$ Y$ l: R
could more readily be coaxed into becoming liver cells.”
2 T( k9 ~; v/ \2 z/ L: RNext, the researchers discovered a set of genes and compounds that can transform these
5 X, l0 R/ g3 @0 w" X7 Qcells into functioning liver cells. And after just a few weeks, the team began to notice a
' N- S0 j0 E  d( Htransformation.
+ w" d; o& O! E) p( d1 ~“The cells began to take on the shape of liver cells, and even started to perform regular livercell
  [% b& d( D. R2 V$ z1 sfunctions,” said UCSF Postdoctoral Scholar Milad Rezvani, MD, the paper’s other lead
0 H5 J! n3 c9 G" J9 P4 @author. “They weren’t fully mature cells yet—but they were on their way.”
/ H4 r( Z; }* E6 mNow that the team was encouraged by these initial results in a dish, they wanted to see what
1 u: R) ~7 E3 b9 _& X8 Uwould happen in an actual liver. So, they transplanted these early-stage liver cells into the1 Q- u( v) Y# f
livers of mice. Over a period of nine months, the team monitored cell function and growth by
7 h& j9 L4 o* s8 C, qmeasuring levels of liver-specific proteins and genes.
" L. k7 z* V$ \! b) G% e& lTwo months post-transplantation, the team noticed a boost in human liver protein levels in the- j! u* Y4 _: A- n6 T/ ]( w
mice, an indication that the transplanted cells were becoming mature, functional liver cells.- K; X8 r$ n; C* G' U
Nine months later, cell growth had shown no signs of slowing down. These results indicate that
2 @* Q/ o6 V% Uthe researchers have found the factors required to successfully regenerate liver tissue.
3 D# i7 {* R7 `“Many questions remain, but the fact that these cells can fully mature and grow for months. I$ E$ k* n) A1 U2 t* N9 \5 @
post-transplantation is extremely promising,” added Dr. Willenbring, associate director of the
- y' q- D. `& T1 V6 i/ A+ IUCSF Liver Center and the paper’s other senior author. “In the future, our technique could* G7 g& {" y; a. G
serve as an alternative for liver-failure patients who don’t require full-organ replacement, or$ R! Q1 x' \' c( h# \8 r
who don’t have access to a transplant due to limited donor organ availability.”- O! R- c* E1 ~: N1 W7 y" Z/ c& }
Other scientists who participated in this research include UCSF researchers Jack Harbell, MD,
" W( I2 W1 `3 Z& k  l, _+ |$ Palso a lead author on the paper, as well as Aras Mattis, MD, PhD, Alan Wolfe and Leslie Benet,
+ p; F& Y( O9 S. P' w2 s+ j, tPhD. Funding was provided by the following: the California Institute for Regenerative Medicine,
3 Q  d2 l2 B" O8 mthe National Institutes of Health, the German Academic Exchange Service, and the Society of; k( p6 Q$ q1 M3 C1 n0 T1 U
University Surgeons.
8 `+ B1 V  {! `/ i1 E2 Z! u% ]" eAbout the Gladstone Institutes
/ @6 J% P: _6 f' ]Gladstone is an independent and nonprofit biomedical-research organization dedicated to$ G; @' [7 M9 X/ n1 }! D$ n
accelerating the pace of scientific discovery and innovation to prevent, treat and cure$ ^' a. k5 O  c4 q
cardiovascular, viral and neurological diseases. Gladstone is affiliated with the University of
4 b4 n, `6 Y0 [! Z2 H! c# ^California, San Francisco.5 y0 o7 f* o7 Q. Q" g; y! b3 |6 z
About UCSF
3 f# e5 o' h9 F# E* T+ y7 gUCSF is a leading university dedicated to promoting health worldwide through advanced: d2 D& Q4 p+ {. Y, p) _
biomedical research, graduate-level education in the life sciences and health professions, and8 c. D1 }3 z0 d+ v; y; U. R' N
excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine,
, b) j1 R0 l" i( \nursing and pharmacy, a graduate division with nationally renowned programs in basic8 B4 ^+ H  c1 [* @# p8 e; x! f/ g
biomedical, translational and population sciences, as well as a preeminent biomedical9 x% n# i8 {2 j7 ~) y+ P" b
research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff
: N+ B. v" o* ^/ W; K" gChildren’s Hospital.
8 z: i7 O' L2 ]" Q  I* y% j7 QPress Contacts7 y4 [4 F" f) ]9 l
Anne Holden
, I: p: x- Q( S# \) Y6 L# YGladstone Institutes" ~! [7 f4 x! {. n5 M/ |9 w( y
415.734.2534
0 M+ ^  S6 R* q0 i/ Zanne.holden@gladstone.ucsf.edu* y0 J8 T' i" {  y8 O$ Y% s
Jeff Norris$ p4 W2 M, @9 j' m
UCSF
. y5 w! q5 f& f* B4 O415.476.8255
6 F3 I$ M! T/ V4 O  }1 c5 t. CJNorris@pubaff.ucsf.edu