エディンバラ大学

The University of Edinburgh

リプログラミング生物学（梶 圭介）
Biology of Reprogramming (KAJI Keisuke)
KAJI Keisuke, Ph.D.
Professor
Biology of Reprogramming
MRC Centre for Regenerative Medicine
Universityof Edinburgh
The Universityof Edinburgh
E-mail address: Keisuke.kaji@ed.ac.uk
URL: http://www.crm.ed.ac.uk/research/group/biology-reprogramming
https://www.ed.ac.uk/regenerative-medicine/research/keisuke-kaji

成熟肝細胞の前駆細胞へのリプログラミング
細胞運命コントロールのメカニズムを探る
2006年、分化した体細胞にたった4つの因子を導入することで人工多能性幹細胞 (iPS細胞)が作製できることが発見されました。iPS細人工多能性幹細胞（iPS細胞）は様々な細胞に分化する能力を有していますが、肝細胞を含め多くの細胞種で大人の体にある成熟した細胞にまで分化させることが難しいのが現状です。最近、我々は成熟肝細胞を特殊な培養条件下に置き、増殖能と再分化能のある前駆胞は誰からも作成することが可能なうえ、様々な細胞に分化できるため、病気の発症に関わる基礎研究、創薬、薬剤毒性試験、再生医細胞にリプログラミングすることに成功しました。このヒトchemically induced liver療など、多くの分野で活用されています。しかしながら、同じ条件を与えても100〜progenitors:1000個に1個程度の細胞しかiPS細胞にはならず、CLiPsは今まで報告されている肝細胞
なぜ、少数の体細胞しかiPS細胞ならないのか、また、この4つの因子がどのように多能性を誘導するのか未だ解明されていません。私株やiPS細胞由来の肝細胞様細胞よりも成熟した肝細胞へと分化できるため、薬物毒性試験、創薬研究、肝細胞移植など様々な用途でたちの研究室ではiPS細胞がどのようにできるのかを研究し、その知見を活かしiPS細胞以外にも医療に役立つ細胞を作製することを目有用であることが期待されます。私たちの研究室ではさらにヒトCLiPsの詳細な解析、培養条件の最適化を進め、医療、創薬に役立つ指しています。
細胞の作製を目指しています。

Molecular mechanismsof reprogramming
Reprogramming
mature hepatocytes
into progenitors
In2006,technology
generate
inducedpluripotent
stemcells
differentiatedsomaticthat
cells
using
onlygenerated
4 factors has
been
While
iPSa cells
have a togreat
potential
to giverise to anycell(iPS)
types
in from
our body,
it is the reality
man
types
fromiPSdeveloped.
iPS cellsand
cannotbe fully
derivedfrom any
individuals
and differentiate
variouscell types,inthey
have alreadyhumanbeen usedforcells are immaturefunctional,including
hepatocytes.
We haveinto
recently
succeeded
reprogramming
maturediseasemodelling,
drug discovery,tests, andregenerative
However, only 1 in
100-1,000undersomatic
cells cangive
hepatocytes
into progenitorsthat toxicology
have unlimited
proliferationand medicine.
efficient re-differentiation
capacities
a special
culturerise
to iPS cells
and whythechemicallyefficiency isinduced
so low, liver
howprogenitors:
the 4 factorsCLiPs
inducehas into
not been
Our groupthan
aimsany
tocondition.
As thesehumancanpluripotency
re-differentiate
more elucidated.
mature hepatocytes
understandthehepatocyte
molecular mechanism
the reprogramming,
improvethe technology
and also
generatefullytoxicology
functionaltests,
otherdrugcellother existingcell lines or of
iPSCs,
we expect that they
can become
an extremely
usefultool fortypes
for medicine,via cellular therapy,
reprogrammingon theaim
knowledge.
screen,usefulhepatocytetransplantation
etc. Ourbasedlab further
to characterize these human CLiPs and optimize the culture
condition and generates useful resource for medicine and drug discovery.

Self-renewal

Differentiated cells+ reprogramming factors?

Hepatosphere with mature
hepatocyte markers
iPS cells
generated from hCliPs
ALB/CYP1A2/DAPI
Heterogeneous, inefficient, immature differentiation in vitro

iPS cells are extremely useful cells that have a potential to make any cell types like embryonic stem (ES) cells. However, in reality,onlylimited
fully functional
cell atypes
can tobemakegenerated
iPS/EScells to datevitro.
iPSacells
are number
extremelyofusefulcells that havepotential
any cellfrom
types
like embryonicstemin(ES)cells.Directing
However,changes
in reality, of cellular
identity
stilla challenge.
understanding
mechanismsof iPS cell
generationChemicallycan give us
cluesliverof how to
manyiscell
types
generated We
frombelieve
iPSCs/ESCs
are immaturemolecularand not fully
functional, including
hepatocytes.
inducedmanipulate
cellularidentitymoreefficiently
andfaithfully.
progenitors: CLiPs we have recently generated from mature human hepatocytes can keep proliferating over 3 months, and have an

efficient re-differentiation capacity into mature hepatocytes.

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