Scientists Transform Skin Cells into Functioning Liver Cells # t+ V( l# Z+ f+ WJoint Gladstone-UCSF study highlights novel reprogramming method; offers new hope for ) t8 e) f7 |; F. [7 j& Y' Etreating liver failure! [; t; e: B9 N! p4 _8 V
EMBARGOED UNTIL 1PM ET, February 23, 20148 K2 H( t* U" U# C% I5 O+ K" Q; I
SAN FRANCISCO, CA—February 23, 2014—The power of regenerative medicine now allows 8 f2 Z; Q$ B0 D& o( G' z& I* @scientists to transform skin cells into cells that closely resemble heart cells, pancreas cells and : {) [8 ^4 j% L$ A* ?( z0 H% Teven neurons. However, a method to generate cells that are fully mature—a crucial! ^ E' o$ e1 _
prerequisite for life-saving therapies—has proven far more difficult. But now, scientists at the9 Q# p4 o; U5 n5 R9 @
Gladstone Institutes and the University of California, San Francisco (UCSF), have made an 0 C1 O, t& a8 T) P$ R- b. g& ximportant breakthrough: they have discovered a way to transform skin cells into mature, fully. t* M+ d6 y, }5 {; D
functioning liver cells that flourish on their own, even after being transplanted into laboratory - [( [$ k N6 O# sanimals modified to mimic liver failure. d2 k4 t! @# V( @/ c% ZIn previous studies on liver-cell reprogramming, scientists had difficulty getting stem cellderived ! R& x4 x2 D1 Sliver cells to survive once being transplanted into existing liver tissue. But the 7 Z5 A) G5 X; y# zGladstone-UCSF team figured out a way to solve this problem. Writing in the latest issue of the u Z7 U& w# X" M' G+ e
journal Nature, researchers in the laboratories of Gladstone Senior Investigator Sheng Ding, 5 v7 }+ x, b3 A, M, C+ ^PhD, and UCSF Associate Professor Holger Willenbring, MD, PhD, reveal a new cellular5 I l' Z' Z) @. s; J+ D# C5 d
reprogramming method that transforms human skin cells into liver cells that are virtually3 I& }! D6 Z8 u* ]* Z6 K
indistinguishable from the cells that make up native liver tissue. " a4 Q& q0 A' q; A; NThese results offer new hope for the millions of people suffering from, or at risk of developing,! D+ N; A8 x4 N- W/ o
liver failure—an increasingly common condition that results in progressive and irreversible loss - ]/ R2 Y* G) wof liver function. At present, the only option is a costly liver transplant. So, scientists have long 0 v0 \! @3 H1 w- s' K3 v9 b3 t6 Llooked to stem cell technology as a potential alternative. But thus far they have come up# w t( D7 b. s9 [; I+ x
largely empty-handed.& R% m, Y; E* f' A {
“Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order! R y& g* t! ~
to then grow liver cells,” explained Dr. Ding, one of the paper’s senior authors, who is also a . b" z4 N- ?6 S" s% c, _9 A9 Lprofessor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. “However, % W# |% A. t/ X* T1 i& Ygenerating these so-called induced pluripotent stem cells, or iPS cells, and then transforming7 k# O7 z+ }9 ~7 V$ X
them into liver cells wasn’t always resulting in complete transformation. So we thought that, r# u3 |3 v2 m7 t* k8 s& q' crather than taking these skin cells all the way back to a pluripotent, stem cell-like state, ) T' l1 m ^. D( }. E3 U9 @perhaps we could take them to an intermediate phase.” % ?* u9 ]- g' M( X3 |7 IThis research, which was performed jointly at the Roddenberry Center for Stem Cell Research" H7 @5 c" K1 Z5 n$ ^2 l y, s
at Gladstone and the Broad Center of Regeneration Medicine and Stem Cell Research at6 P, i# C/ [& N* {- M
UCSF, involved using a ‘cocktail’ of reprogramming genes and chemical compounds to ( ~2 o: Q' f5 P2 e! ztransform human skin cells into cells that resembled the endoderm. Endoderm cells are cells- O7 f( Y# E; ]3 h
that eventually mature into many of the body’s major organs—including the liver.3 d/ \ s) d/ Y f/ L$ l
“Instead of taking the skin cells back to the beginning, we took them only part way, creating: C; ~& Z7 K& M& W
endoderm-like cells,” added Gladstone and CIRM Postdoctoral Scholar Saiyong Zhu, PhD, one; r2 O. U& t% _" B, _
of the paper’s lead authors. “This step allowed us to generate a large reservoir of cells that' V4 C2 S2 b+ }+ L% D2 \
could more readily be coaxed into becoming liver cells.” . u* z8 e% X2 q) G3 x; t4 MNext, the researchers discovered a set of genes and compounds that can transform these 5 B$ p" O2 ^7 w3 acells into functioning liver cells. And after just a few weeks, the team began to notice a ( Z6 w+ _, K$ @transformation. - ?" _; F" V/ r B5 `5 {/ e“The cells began to take on the shape of liver cells, and even started to perform regular livercell / H3 P" g4 Q. O9 J+ x7 h4 Pfunctions,” said UCSF Postdoctoral Scholar Milad Rezvani, MD, the paper’s other lead # y8 l' N' Z# e0 l( W6 k: ^author. “They weren’t fully mature cells yet—but they were on their way.”; E. N" z" l. s5 X' m: q
Now that the team was encouraged by these initial results in a dish, they wanted to see what 3 B5 B* @" B' n# M+ e5 S. x Pwould happen in an actual liver. So, they transplanted these early-stage liver cells into the6 l+ O$ q$ U" [& ~5 a2 a+ x
livers of mice. Over a period of nine months, the team monitored cell function and growth by Q+ e, r& v1 T& ^- L
measuring levels of liver-specific proteins and genes. ; k3 [. q! l+ R% [% p0 }$ N) cTwo months post-transplantation, the team noticed a boost in human liver protein levels in the5 J1 A& j$ C$ q5 a9 T5 h$ W
mice, an indication that the transplanted cells were becoming mature, functional liver cells. G+ o& F3 ~8 ^0 X( w6 h9 \" v
Nine months later, cell growth had shown no signs of slowing down. These results indicate that- }8 c2 |, M8 @" e
the researchers have found the factors required to successfully regenerate liver tissue. ( T0 o$ m3 }; l“Many questions remain, but the fact that these cells can fully mature and grow for months. ^( b$ k P2 f+ |3 ]2 R
post-transplantation is extremely promising,” added Dr. Willenbring, associate director of the ! `$ d- b" ]2 R5 B; `9 d G' uUCSF Liver Center and the paper’s other senior author. “In the future, our technique could $ `8 U1 a; j5 z& E) Yserve as an alternative for liver-failure patients who don’t require full-organ replacement, or1 Y6 N/ o& m7 F( [4 @ ]) m
who don’t have access to a transplant due to limited donor organ availability.”2 i, t e+ X4 L2 A8 K$ P, y7 J- p1 i
Other scientists who participated in this research include UCSF researchers Jack Harbell, MD, / n6 u2 v; }7 V+ jalso a lead author on the paper, as well as Aras Mattis, MD, PhD, Alan Wolfe and Leslie Benet,/ r" h v: t9 Y" j1 |7 I, }
PhD. Funding was provided by the following: the California Institute for Regenerative Medicine,4 f8 f& ?4 q' _9 X$ s/ ~3 p0 S
the National Institutes of Health, the German Academic Exchange Service, and the Society of & I! @" q" A1 E8 C/ `University Surgeons.- V: D* j; t6 t1 }
About the Gladstone Institutes 3 Z0 |7 s9 o" s0 j$ o& o/ e2 b3 ~Gladstone is an independent and nonprofit biomedical-research organization dedicated to# [7 C( F4 C9 g' Q8 O" H$ B
accelerating the pace of scientific discovery and innovation to prevent, treat and cure & g+ z5 W( R' lcardiovascular, viral and neurological diseases. Gladstone is affiliated with the University of 3 d' T5 r( Q- P( H1 tCalifornia, San Francisco. & a& p1 j1 F9 K8 B) m9 rAbout UCSF7 @1 C. }! X4 ^ R3 c$ G# T
UCSF is a leading university dedicated to promoting health worldwide through advanced0 d! l* c9 |# K5 u
biomedical research, graduate-level education in the life sciences and health professions, and5 i7 y5 A' h2 W* B7 W
excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, ) P5 Z5 v) j9 x( ]% A: I$ Cnursing and pharmacy, a graduate division with nationally renowned programs in basic, U+ [; G* k4 F5 C
biomedical, translational and population sciences, as well as a preeminent biomedical* T& t# f1 o1 u" o+ P
research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff 9 y n7 ]/ m3 v$ ]" o3 dChildren’s Hospital. z/ f# m( D$ k
Press Contacts) D/ y/ F$ c% t
Anne Holden5 j# z ?2 O" y+ d% X8 D
Gladstone Institutes 6 W) F+ k' ~ M8 E. [, p0 n415.734.2534 # P' n4 O- z% y* D lanne.holden@gladstone.ucsf.edu* d. Y0 E# k3 p5 h+ i
Jeff Norris 4 Y/ L a6 L: F- Y& U, sUCSF, d( [% [/ B; e, O0 t5 G
415.476.8255/ ]1 O. ~5 O# s d( N8 Q1 {1 w+ C# ] JNorris@pubaff.ucsf.edu