Scientists Transform Skin Cells into Functioning Liver Cells

ceazon

Scientists Transform Skin Cells into Functioning Liver Cells. \3 ~0 Q5 \1 H, u
Joint Gladstone-UCSF study highlights novel reprogramming method; offers new hope for
4 Y1 I1 M( w8 }4 f4 j1 b( f" Ztreating liver failure) }, q, b% e9 x4 Q* C
EMBARGOED UNTIL 1PM ET, February 23, 2014! d3 Y4 e. ^" r& {/ R
SAN FRANCISCO, CA—February 23, 2014—The power of regenerative medicine now allows
/ ?( @$ Q  V0 T  ]' B7 N( l$ escientists to transform skin cells into cells that closely resemble heart cells, pancreas cells and* [4 e9 f$ x( l0 p! t% N% u- V
even neurons. However, a method to generate cells that are fully mature—a crucial/ r8 h5 `7 V* }) l) w2 a* v; R( r9 k' A
prerequisite for life-saving therapies—has proven far more difficult. But now, scientists at the% V: E1 y/ k  q% J7 N2 Z+ ~6 n
Gladstone Institutes and the University of California, San Francisco (UCSF), have made an4 z: f9 J% b8 R9 t  Q3 ^! q
important breakthrough: they have discovered a way to transform skin cells into mature, fully' g* }+ `! G/ u8 C& I! M- ^
functioning liver cells that flourish on their own, even after being transplanted into laboratory; E! O5 x% k- |3 D2 R
animals modified to mimic liver failure.4 B; M' R4 [+ I# t! S- ?/ \) A
In previous studies on liver-cell reprogramming, scientists had difficulty getting stem cellderived  m6 X' w1 u" E0 h# ~9 |' @
liver cells to survive once being transplanted into existing liver tissue. But the3 \  W0 a1 e9 @, P
Gladstone-UCSF team figured out a way to solve this problem. Writing in the latest issue of the
2 n- F4 x% \! {, ^, E5 d- tjournal Nature, researchers in the laboratories of Gladstone Senior Investigator Sheng Ding,7 [4 w+ q0 ]( d* ]
PhD, and UCSF Associate Professor Holger Willenbring, MD, PhD, reveal a new cellular8 [' W2 k- k+ u! E. t. _( x* x
reprogramming method that transforms human skin cells into liver cells that are virtually
9 B3 o1 k6 u; i# v( Findistinguishable from the cells that make up native liver tissue.
' \/ I% w+ L# H0 e  I6 sThese results offer new hope for the millions of people suffering from, or at risk of developing,: q$ u+ b  d. F# h" o% r
liver failure—an increasingly common condition that results in progressive and irreversible loss* s4 i2 F8 V" ]% K: i, ?+ o+ O. G
of liver function. At present, the only option is a costly liver transplant. So, scientists have long. w, c. w  @7 K* Z( k
looked to stem cell technology as a potential alternative. But thus far they have come up
+ h8 _5 S7 M! \9 _5 o* ilargely empty-handed.0 D  c5 T5 {- w5 |/ E6 d
“Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order
. h" `- {8 P% r2 c* hto then grow liver cells,” explained Dr. Ding, one of the paper’s senior authors, who is also a
) ]* g! t* n* A8 b9 l) T* r: [professor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. “However,
& \/ P* L1 I4 w( z' ugenerating these so-called induced pluripotent stem cells, or iPS cells, and then transforming
" A7 H4 C7 t6 D0 y: d6 lthem into liver cells wasn’t always resulting in complete transformation. So we thought that,
$ w  [& @/ {  R. orather than taking these skin cells all the way back to a pluripotent, stem cell-like state,
. o3 }2 Z& ~1 P) b+ F; Kperhaps we could take them to an intermediate phase.”. Z( l- j9 F, ]" c
This research, which was performed jointly at the Roddenberry Center for Stem Cell Research' O( j9 s$ ?% M/ A- \
at Gladstone and the Broad Center of Regeneration Medicine and Stem Cell Research at
+ k: z3 A1 u6 }3 m+ W& DUCSF, involved using a ‘cocktail’ of reprogramming genes and chemical compounds to' _5 U. o4 R6 I8 V  B
transform human skin cells into cells that resembled the endoderm. Endoderm cells are cells
( o! z. D8 u' T  Mthat eventually mature into many of the body’s major organs—including the liver.4 \, A$ s* M, x, \0 b2 Y
“Instead of taking the skin cells back to the beginning, we took them only part way, creating
9 s" \4 @3 w# Y& L+ [1 lendoderm-like cells,” added Gladstone and CIRM Postdoctoral Scholar Saiyong Zhu, PhD, one
7 K3 f0 f" V* U3 {" `of the paper’s lead authors. “This step allowed us to generate a large reservoir of cells that
( ~4 L, a3 `. t' O. w( ucould more readily be coaxed into becoming liver cells.”
& u' {& w" S* @; z1 LNext, the researchers discovered a set of genes and compounds that can transform these+ J& ]0 w! l4 _! h' H" p$ j5 m
cells into functioning liver cells. And after just a few weeks, the team began to notice a
7 k1 L% |) D8 r7 O% k; `& ]6 Rtransformation.1 ~% z# R: k! D$ L
“The cells began to take on the shape of liver cells, and even started to perform regular livercell
2 ?) V5 P) M+ Gfunctions,” said UCSF Postdoctoral Scholar Milad Rezvani, MD, the paper’s other lead$ q4 N) R8 ^" s+ s4 B+ \( z+ Q
author. “They weren’t fully mature cells yet—but they were on their way.”
  m7 x/ h) W- y/ XNow that the team was encouraged by these initial results in a dish, they wanted to see what
: K5 `8 Z; i4 K$ E" p' p: Q% ?would happen in an actual liver. So, they transplanted these early-stage liver cells into the" I% `' w, ?# G7 a
livers of mice. Over a period of nine months, the team monitored cell function and growth by0 k' x! r5 l. a  J- a; s! Z1 O, u( j6 \
measuring levels of liver-specific proteins and genes.' K. G) E2 g4 n: O
Two months post-transplantation, the team noticed a boost in human liver protein levels in the
* n; S) n# N0 t+ |mice, an indication that the transplanted cells were becoming mature, functional liver cells.
( E  ?' r* l7 |/ ~: w" X" \Nine months later, cell growth had shown no signs of slowing down. These results indicate that
( a* ~% F' O# h5 k; ?the researchers have found the factors required to successfully regenerate liver tissue.
" i8 W' K5 _4 L" S“Many questions remain, but the fact that these cells can fully mature and grow for months
$ [6 \; Q+ L  }  m- c) B; z7 rpost-transplantation is extremely promising,” added Dr. Willenbring, associate director of the/ S( M7 E7 ~0 }9 q( e1 o$ q/ C
UCSF Liver Center and the paper’s other senior author. “In the future, our technique could. |& W) k' k" ]0 E& C5 e
serve as an alternative for liver-failure patients who don’t require full-organ replacement, or- g. a$ u, ~$ v& C* J: W; F
who don’t have access to a transplant due to limited donor organ availability.”
9 d, f: j: S- m! P6 Y# dOther scientists who participated in this research include UCSF researchers Jack Harbell, MD,5 q% q* y% \+ d( h# R, J& L
also a lead author on the paper, as well as Aras Mattis, MD, PhD, Alan Wolfe and Leslie Benet,/ ^  g* r; r$ p$ G
PhD. Funding was provided by the following: the California Institute for Regenerative Medicine,
! C8 e3 l/ G; l+ |. Wthe National Institutes of Health, the German Academic Exchange Service, and the Society of
8 [: P3 k6 w6 {& |University Surgeons.
4 [/ d: O: b, _- n5 p3 VAbout the Gladstone Institutes
: P+ d3 a- Y( |) N& O4 nGladstone is an independent and nonprofit biomedical-research organization dedicated to, a% I5 N& u! _' F$ e
accelerating the pace of scientific discovery and innovation to prevent, treat and cure
; u& ?5 \5 X& X3 ?! x+ x) Bcardiovascular, viral and neurological diseases. Gladstone is affiliated with the University of; h. [9 b1 K9 r
California, San Francisco.' t* U# y" f0 b- M
About UCSF
4 @: p+ ]& _: F$ T1 B% M+ sUCSF is a leading university dedicated to promoting health worldwide through advanced
' D. I8 f) x4 B/ u6 Pbiomedical research, graduate-level education in the life sciences and health professions, and
7 T8 g9 s3 V- ^7 s- k' O& Fexcellence in patient care. It includes top-ranked graduate schools of dentistry, medicine,
6 E) l/ f, I$ M+ |5 z# {' L4 ?nursing and pharmacy, a graduate division with nationally renowned programs in basic
9 b0 t- T2 I8 _biomedical, translational and population sciences, as well as a preeminent biomedical4 j- g2 G, r3 Y- \* [' `, ~
research enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff
( n- @  b, e& ~Children’s Hospital.# p8 \) M3 W$ y3 j) t- R$ X
Press Contacts
* }6 h( M5 U4 G" uAnne Holden
: l  U9 a  p( K  D9 }- XGladstone Institutes1 F; k! `- R1 X& e0 M
415.734.2534
8 p8 B7 s& \3 ^. L: l* k0 G7 Manne.holden@gladstone.ucsf.edu" `5 g$ T. \: S& ~
Jeff Norris
3 y" S$ [0 W1 m2 a1 LUCSF( v& N/ O+ b3 ~+ U  J" M
415.476.8255
8 I3 j5 r, J; B/ Z  h9 U. M+ pJNorris@pubaff.ucsf.edu