Scientists Transform Skin Cells into Functioning Liver Cells

ceazon

Scientists Transform Skin Cells into Functioning Liver Cells# w, W/ e3 N1 |1 @9 O
Joint Gladstone-UCSF study highlights novel reprogramming method; offers new hope for
8 P8 c1 K  m9 L- V) s+ Gtreating liver failure
: p( M- @/ A2 M1 z  [7 t) J8 ^  fEMBARGOED UNTIL 1PM ET, February 23, 2014/ T4 F9 F, ^4 J! Y1 e" m9 W, F
SAN FRANCISCO, CA—February 23, 2014—The power of regenerative medicine now allows  ?5 [0 t) d, A# ^
scientists to transform skin cells into cells that closely resemble heart cells, pancreas cells and9 ]3 F5 p: J( D/ Q0 I$ a
even neurons. However, a method to generate cells that are fully mature—a crucial
- [( l7 Y4 ]" Y+ ~4 c! Cprerequisite for life-saving therapies—has proven far more difficult. But now, scientists at the
) M% k  u& l+ ]+ s: o0 g* ]Gladstone Institutes and the University of California, San Francisco (UCSF), have made an
. r) R2 a" Y+ m( \3 f8 Eimportant breakthrough: they have discovered a way to transform skin cells into mature, fully
* }! n0 r1 m* e* Qfunctioning liver cells that flourish on their own, even after being transplanted into laboratory1 Y! H% ^7 @& j4 V5 W
animals modified to mimic liver failure./ O# x/ T) k. v# F- \
In previous studies on liver-cell reprogramming, scientists had difficulty getting stem cellderived
( \  W, K, q- D/ }( J8 lliver cells to survive once being transplanted into existing liver tissue. But the6 h0 M7 p5 o& u& t
Gladstone-UCSF team figured out a way to solve this problem. Writing in the latest issue of the
! Y" a9 m" z) L1 t7 Qjournal Nature, researchers in the laboratories of Gladstone Senior Investigator Sheng Ding,& N1 h8 B3 G0 ^" R: X
PhD, and UCSF Associate Professor Holger Willenbring, MD, PhD, reveal a new cellular
. q( f0 R/ b9 Ureprogramming method that transforms human skin cells into liver cells that are virtually
% C& D% e) V) |7 I  j$ vindistinguishable from the cells that make up native liver tissue.
7 C. \  l$ N1 WThese results offer new hope for the millions of people suffering from, or at risk of developing,
; k2 b) K8 J) w& h4 |/ `2 Iliver failure—an increasingly common condition that results in progressive and irreversible loss1 J6 j- I% }9 _2 q* t' i4 f- h
of liver function. At present, the only option is a costly liver transplant. So, scientists have long
- v9 G# w# ~8 q3 llooked to stem cell technology as a potential alternative. But thus far they have come up# z0 g7 m- z3 n! k/ R0 P
largely empty-handed.
. Y( |* k1 _% c8 Y; a3 l“Earlier studies tried to reprogram skin cells back into a pluripotent, stem cell-like state in order
( S& E5 o5 z6 ?4 {1 q% e" q3 S. uto then grow liver cells,” explained Dr. Ding, one of the paper’s senior authors, who is also a
9 k- R" t5 e% n: Tprofessor of pharmaceutical chemistry at UCSF, with which Gladstone is affiliated. “However,, L! r9 |8 X: |% s$ u; d+ A3 n) R2 s
generating these so-called induced pluripotent stem cells, or iPS cells, and then transforming& Z  k  d7 ^# T; ~9 u- F/ I
them into liver cells wasn’t always resulting in complete transformation. So we thought that,, Y- `- f- y% H5 z1 i# e
rather than taking these skin cells all the way back to a pluripotent, stem cell-like state,
  n% }" k# e6 k8 L( |perhaps we could take them to an intermediate phase.”
2 y6 W- N+ l" YThis research, which was performed jointly at the Roddenberry Center for Stem Cell Research1 F7 ~) S4 w) A! C! A1 [' H
at Gladstone and the Broad Center of Regeneration Medicine and Stem Cell Research at7 K1 O  Y0 M& \! a# j. u2 y5 K
UCSF, involved using a ‘cocktail’ of reprogramming genes and chemical compounds to# u0 a* l* b  h9 ~/ r
transform human skin cells into cells that resembled the endoderm. Endoderm cells are cells- f7 p& o, F& _& Z7 F$ u& W. _0 {" X
that eventually mature into many of the body’s major organs—including the liver.! m9 G4 S' ^/ m$ A& [( T
“Instead of taking the skin cells back to the beginning, we took them only part way, creating" u* o5 L& L6 B& Z2 t7 V4 z
endoderm-like cells,” added Gladstone and CIRM Postdoctoral Scholar Saiyong Zhu, PhD, one
7 W- M/ U/ H: v: O4 i; s2 oof the paper’s lead authors. “This step allowed us to generate a large reservoir of cells that
% h0 S' W4 l& c; Gcould more readily be coaxed into becoming liver cells.”/ H" C) g; `* @/ M0 q
Next, the researchers discovered a set of genes and compounds that can transform these, p$ L. |: D0 C0 X4 p$ v
cells into functioning liver cells. And after just a few weeks, the team began to notice a
( O+ o1 u* N# A4 x4 k$ _. ttransformation.
6 t$ S7 Y; T$ F6 h: W8 z/ M“The cells began to take on the shape of liver cells, and even started to perform regular livercell; X! S# M  X* o/ ^# A. b
functions,” said UCSF Postdoctoral Scholar Milad Rezvani, MD, the paper’s other lead
7 H  O1 o5 f3 N9 x$ v0 wauthor. “They weren’t fully mature cells yet—but they were on their way.”% V+ `1 p7 ?; f2 }( p
Now that the team was encouraged by these initial results in a dish, they wanted to see what
0 T* O" C+ \1 x9 c- twould happen in an actual liver. So, they transplanted these early-stage liver cells into the
" R% h7 l2 S! E- U# M. vlivers of mice. Over a period of nine months, the team monitored cell function and growth by* [! u9 q& d( F9 K# }
measuring levels of liver-specific proteins and genes., Q* o2 ^4 ]: [, e5 `7 c9 T  J6 m: i4 x
Two months post-transplantation, the team noticed a boost in human liver protein levels in the
; |6 l8 |* V% f6 ^! pmice, an indication that the transplanted cells were becoming mature, functional liver cells.6 O! F+ E( C! Q' L' t# ~4 A
Nine months later, cell growth had shown no signs of slowing down. These results indicate that
, C) \' |3 }* Bthe researchers have found the factors required to successfully regenerate liver tissue.
2 P& W- G# T! c$ C“Many questions remain, but the fact that these cells can fully mature and grow for months
- l9 P4 d: I1 o1 ^- i4 L5 Z3 G8 a8 ]post-transplantation is extremely promising,” added Dr. Willenbring, associate director of the% w* W4 W+ ~6 z' l2 _
UCSF Liver Center and the paper’s other senior author. “In the future, our technique could
. ~6 v" b* i4 I! c! r4 d8 Lserve as an alternative for liver-failure patients who don’t require full-organ replacement, or; K, v- H, ?- T8 u
who don’t have access to a transplant due to limited donor organ availability.”
; o; S3 D5 R6 y8 c; d3 {6 }7 |Other scientists who participated in this research include UCSF researchers Jack Harbell, MD,% C4 C2 d  K5 N; c$ C
also a lead author on the paper, as well as Aras Mattis, MD, PhD, Alan Wolfe and Leslie Benet," d8 A% q; M2 r3 B/ i
PhD. Funding was provided by the following: the California Institute for Regenerative Medicine,  y4 ?' o. U. K  m$ W  P
the National Institutes of Health, the German Academic Exchange Service, and the Society of
! g2 ], v2 ~% Z- PUniversity Surgeons.
& G( Z) R: C/ W5 m' N1 ]' \About the Gladstone Institutes0 p/ V- k4 N6 N+ M9 s0 Q! U7 A
Gladstone is an independent and nonprofit biomedical-research organization dedicated to- s. v3 s4 t- }
accelerating the pace of scientific discovery and innovation to prevent, treat and cure
5 E+ Y4 {. B( F9 gcardiovascular, viral and neurological diseases. Gladstone is affiliated with the University of
8 W0 o9 J2 q$ K6 x8 a# w5 |California, San Francisco.
) Q, C& c0 m2 A. Z& q- Z" VAbout UCSF1 k" ]1 c) G% _' I; f
UCSF is a leading university dedicated to promoting health worldwide through advanced
* N: I7 p3 I% u6 {, ~9 w4 ~+ Pbiomedical research, graduate-level education in the life sciences and health professions, and6 [; x0 d$ N3 F4 a
excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine,4 X7 z5 Y5 ]; X0 R$ |& K
nursing and pharmacy, a graduate division with nationally renowned programs in basic
& }. y0 B, `; q8 o1 z8 Rbiomedical, translational and population sciences, as well as a preeminent biomedical
" k# \0 X$ M. x' C" ^; l% ]" aresearch enterprise and two top-ranked hospitals, UCSF Medical Center and UCSF Benioff! O3 M* `- Z, x* P. b
Children’s Hospital.& n; b' O2 C% Y
Press Contacts' F% w& G0 M9 |
Anne Holden0 L8 P7 Z0 `  |( O3 n8 B
Gladstone Institutes
) N2 ^+ N0 q8 z% ~7 Y! m415.734.25348 N  l7 F% J. Z* v# d
anne.holden@gladstone.ucsf.edu
4 ^" \8 R, J: o) q( ~% W4 ZJeff Norris
0 x9 W" Q& O' N; q3 h7 @UCSF
4 {5 U# C- s% _- @  P415.476.8255* A2 i9 a: ^3 d5 n* c8 }2 n
JNorris@pubaff.ucsf.edu