Scientists Transform Skin Cells into Functioning Liver Cells

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Scientists Transform Skin Cells into Functioning Liver Cells
/ O/ l& B! \/ aJoint Gladstone-UCSF study highlights novel reprogramming method; offers new hope for7 U3 C/ X) G5 g6 {8 U/ C* C
treating liver failure) U. b+ Z& p* {2 Z; `
EMBARGOED UNTIL 1PM ET, February 23, 2014* U0 z8 M" P& c' w/ [
SAN FRANCISCO, CA—February 23, 2014—The power of regenerative medicine now allows
- \2 i' t; t( a5 A3 N4 Lscientists to transform skin cells into cells that closely resemble heart cells, pancreas cells and
7 y  o" f- a6 `9 q) Ceven neurons. However, a method to generate cells that are fully mature—a crucial
9 m9 E) Q1 R( D! J, `* ]7 qprerequisite for life-saving therapies—has proven far more difficult. But now, scientists at the. c) c  v( U9 P! ^9 d( J! a+ S% }
Gladstone Institutes and the University of California, San Francisco (UCSF), have made an
+ x. ]7 ~2 S9 E6 B: i1 w# oimportant breakthrough: they have discovered a way to transform skin cells into mature, fully- R1 K0 R& Z* o7 b" _  I! C
functioning liver cells that flourish on their own, even after being transplanted into laboratory5 W% r- G( W7 m$ @, `) N9 h1 d
animals modified to mimic liver failure.+ K1 b7 W+ m* z, i5 x/ W5 q
In previous studies on liver-cell reprogramming, scientists had difficulty getting stem cellderived9 R( p9 ?$ L4 M5 n6 ?* B: m
liver cells to survive once being transplanted into existing liver tissue. But the
, \3 b  u" Z! b) _Gladstone-UCSF team figured out a way to solve this problem. Writing in the latest issue of the8 p3 P# r9 J7 I6 C( [
journal Nature, researchers in the laboratories of Gladstone Senior Investigator Sheng Ding,
% F, s. W4 T4 I; _8 C. H* q' OPhD, and UCSF Associate Professor Holger Willenbring, MD, PhD, reveal a new cellular' t* z1 P* z5 m5 G* [
reprogramming method that transforms human skin cells into liver cells that are virtually
2 H. O# [+ J9 a& A/ T8 Q: n( z8 K2 Uindistinguishable from the cells that make up native liver tissue.) {2 o: z3 D! k% C, R
These results offer new hope for the millions of people suffering from, or at risk of developing,! _# l6 g* g, N6 @7 ]  z
liver failure—an increasingly common condition that results in progressive and irreversible loss; G. x! {- M. p  Y& k+ A
of liver function. At present, the only option is a costly liver transplant. So, scientists have long9 C' c' h& w3 s
looked to stem cell technology as a potential alternative. But thus far they have come up
' H0 O/ x6 |" {* q* j& B  ?. @- `largely empty-handed.
) P. b9 W2 b. X“Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order; h+ B( U: x2 s6 w: X
to then grow liver cells,” explained Dr. Ding, one of the paper’s senior authors, who is also a+ |4 E7 t9 T/ b$ Z& Y( ?- @9 [
professor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. “However,
1 o2 h* G1 g# e) H9 zgenerating these so-called induced pluripotent stem cells, or iPS cells, and then transforming
0 T) |1 N" W5 p; ^$ e+ gthem into liver cells wasn’t always resulting in complete transformation. So we thought that,
3 S* P9 a) H; w" h# @! Urather than taking these skin cells all the way back to a pluripotent, stem cell-like state,
' i9 B' Q4 U! J5 zperhaps we could take them to an intermediate phase.”3 b8 J8 {. V  z4 {4 R: w+ Y$ ^
This research, which was performed jointly at the Roddenberry Center for Stem Cell Research
! r) u3 W) V1 C+ _$ xat Gladstone and the Broad Center of Regeneration Medicine and Stem Cell Research at3 U8 A% w" B- l$ Q+ J5 V
UCSF, involved using a ‘cocktail’ of reprogramming genes and chemical compounds to
" q% a0 v% Q7 b/ G! `transform human skin cells into cells that resembled the endoderm. Endoderm cells are cells0 R! P, c# t5 h# n+ K
that eventually mature into many of the body’s major organs—including the liver.
" f9 P' j9 p- z: y) d$ O  f“Instead of taking the skin cells back to the beginning, we took them only part way, creating
0 i6 s+ V, B( f: p5 A# hendoderm-like cells,” added Gladstone and CIRM Postdoctoral Scholar Saiyong Zhu, PhD, one
" V" [3 s" P$ v. r, R$ Q$ d4 s% ^of the paper’s lead authors. “This step allowed us to generate a large reservoir of cells that) n, `$ |) v- ^9 S, L' B/ l
could more readily be coaxed into becoming liver cells.”& r' u2 @' H' _. ?, v+ R, v" q8 P% D
Next, the researchers discovered a set of genes and compounds that can transform these
5 c5 d- c" @1 Y$ ^1 }1 ~  p$ fcells into functioning liver cells. And after just a few weeks, the team began to notice a2 }' m; H4 a) {9 t7 r# n
transformation.0 m- l: f( S, U' H4 ?$ f9 q( D# n
“The cells began to take on the shape of liver cells, and even started to perform regular livercell
, {& d- A3 d) w5 P: P6 t7 f7 Ifunctions,” said UCSF Postdoctoral Scholar Milad Rezvani, MD, the paper’s other lead
0 s( {% h$ M0 Eauthor. “They weren’t fully mature cells yet—but they were on their way.”
& M' h9 b9 F3 V5 l, _& V& hNow that the team was encouraged by these initial results in a dish, they wanted to see what
' z7 ^; R5 q7 @- Z& j- k: {would happen in an actual liver. So, they transplanted these early-stage liver cells into the
1 c5 @/ o* ~2 ~% M9 c% S) p$ dlivers of mice. Over a period of nine months, the team monitored cell function and growth by
5 m( Z# l7 m: b: }& y  c6 l6 L# Mmeasuring levels of liver-specific proteins and genes.
  O* D" Y% r' C# a0 TTwo months post-transplantation, the team noticed a boost in human liver protein levels in the
! I8 d8 q/ C' H4 w$ s5 |7 `0 zmice, an indication that the transplanted cells were becoming mature, functional liver cells.
3 A0 b& f1 O; Q+ x) gNine months later, cell growth had shown no signs of slowing down. These results indicate that
  N3 ?; o" y, i9 R) \! P) Tthe researchers have found the factors required to successfully regenerate liver tissue.
) u; }, M* H$ Q) R& E; |/ b- a“Many questions remain, but the fact that these cells can fully mature and grow for months( m* W) W( K5 [# r
post-transplantation is extremely promising,” added Dr. Willenbring, associate director of the" i) }# |. w" F- |1 g
UCSF Liver Center and the paper’s other senior author. “In the future, our technique could
) V4 w* d9 v6 [- p" g2 w7 gserve as an alternative for liver-failure patients who don’t require full-organ replacement, or
- T1 c; N3 H  A0 e. v4 kwho don’t have access to a transplant due to limited donor organ availability.”
" U9 `0 L2 Z' ^+ ]* v/ f$ ~" COther scientists who participated in this research include UCSF researchers Jack Harbell, MD,# i6 i5 Y( t5 g1 X6 z" q
also a lead author on the paper, as well as Aras Mattis, MD, PhD, Alan Wolfe and Leslie Benet,
+ }$ H# w7 w  P' \PhD. Funding was provided by the following: the California Institute for Regenerative Medicine,) E& _3 A6 h5 F6 k' r6 W( L
the National Institutes of Health, the German Academic Exchange Service, and the Society of
% [5 |% k6 l$ M: KUniversity Surgeons.
3 O/ j: s) @% X7 M/ ]About the Gladstone Institutes# y; \; D' X. m& ^2 ^% E
Gladstone is an independent and nonprofit biomedical-research organization dedicated to
% `6 \! x2 z# e0 m$ Xaccelerating the pace of scientific discovery and innovation to prevent, treat and cure. W0 A! T: f1 Q+ d# `
cardiovascular, viral and neurological diseases. Gladstone is affiliated with the University of0 }) o( }6 U% t7 \$ O& A' l
California, San Francisco.
* Z, Y9 g) e% I7 e1 }. a; B1 m8 a" rAbout UCSF9 i; T. ]8 F6 [" Q9 ~
UCSF is a leading university dedicated to promoting health worldwide through advanced, `, Y" ^: W/ Z, j" y
biomedical research, graduate-level education in the life sciences and health professions, and' g. u$ h+ Z$ w9 \; d* w
excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine,3 C: L3 V) f+ D5 z
nursing and pharmacy, a graduate division with nationally renowned programs in basic" r/ v; h/ z" h; h3 U9 ~
biomedical, translational and population sciences, as well as a preeminent biomedical4 @" [  z* o% o2 s" g) q7 C, Q
research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff+ m- c: s: k# }) i; Y2 M
Children’s Hospital.
9 z, h4 M: A/ d2 }' e& b# r* EPress Contacts* `! i! E$ h0 i
Anne Holden4 K5 {) `' [" v
Gladstone Institutes
) b- d3 w; k" \; b5 |415.734.2534
; u* m+ Z2 O0 v7 A0 `anne.holden@gladstone.ucsf.edu% f! c5 Q; B% \$ `  `
Jeff Norris
" e) U4 C  H! y" x. qUCSF4 \* N6 u& M5 t9 G
415.476.8255
& S3 ^" t) t% P( J. j1 mJNorris@pubaff.ucsf.edu