Pyle Stem Cell Therapy Part 1

8/16/2019 Pyle Stem Cell Therapy Part 1

1/21

Role of Stem Cells in Muscle

Regeneration and Therapy for

DMD

April Pyle, Ph.D.

Associate Professor

UCLA Department of Microiology, !mmunology

and Molecular "enetics

UCLA #road Stem Cell Research Center

UCLA Center for Duchenne Muscular Dystrophy


2/21

Stem Cells$ Properties, Sources %

Rele&ance to DMD

'


3/21

A scientific (ournal )The Stem Cell Chronicle* is

holding a contest for the est ans+er to the

follo+ing uestions on stem cells.

Ta-e a minute and sumit an entry to the contest y

ans+ering the follo+ing$

. AR/ ALL ST/M C/LLS T0/ SAM/1

'. 20AT R/"ULAT/S ST/M C/LL 3AT/1

4ne Minute 2rite

5


4/21

replicate itself

Stem Cell Properties

Self6rene+

2hat is stem cell1

A single cell that can

Differenti

differentiate into many

cell types.

or

7


5/21

OriginAbility to

form othercell types

AbundanceAverage

half-life inculture

/mryonic

8/S, couldform all cell

types9pluripotent

!n &itroartifact

deri&ed from!CM

!mmortal

AdultL!M!T/Dpotential9

multipotent

Rare, tissuespecific Limited

Potency, :umer % Sur&i&al

;


6/21

OriginAbility to

form tumors(teratomas)

Control of differentiation

Clinicaluse

/mryonic 8/SPoorly

understood Acti&e6


7/21

Adult Stem Cells % Sources

? Satellite @muscle

? Myolast @muscle

? Mesangiolast @lood &essels

? Mesenchymal @stromal, one marro+,

fat, etc.

? CD55 positi&e @lood or muscle

? Pericytes @lood &essel or muscle

? Muscle Deri&ed @muscle

? Side Population @lood or muscle

B


8/21

Locating the Satellite Cell in Muscle

? Located et+een the sarcolemma and thee=tracellular matri= of muscle.

? 3ollo+ing in(ury, satellite cells di&ide and gi&e rise

to myolasts.


9/21

Accumulation of Satellite Cells Around the Motor /nd

Plate in an !solated Soleus Myofier

Legend$

Pa=B @green

Satellite cells @arro+s

6ungaroto=in @red

:euromuscular (unction @arro+head

E


10/21

Satellite Cell Myogenesis % Mar-er Progression

Satellite Cell Myofier Myolast

Fuiescent Acti&ated Proliferati&e Commitment todifferentiation

3usion into myotue

Maturation intomyofier

CD57

Pa=B

Myf;

MyoD

Myogenin

MLC53

Molecular Mar-ers /=pressed During Satellite Cell Maturation

G


11/21

Tools for Study and !solation of Satellite Cells


12/21

The Satellite Cell :iche

Signaling +ithin the !mmediate :iche

'


13/21

Harious Cell Types !n&ol&ed in Muscle Regenerat

#lood &esselsIcapillaries

Regenerating myofiers

Macrophages

Satellite cells3irolasts

Angiogenic

endothelial

cells

Differentiating myocytes

3i

pro

5


14/21

Mouse S-eletal Muscle Regeneration

Unin(ured G days 5G da; days

Days Post !n(ury

7


15/21

/mryonic &ersus !nduced Pluripotent Stem Cel

#lastocyst/mryonic Stem Cell @/SC Differentiate

!nduced Pluripotent Stem Cell @iPSC

Reprogramming @adult ac- to pluripotent cell$

4&ere=pression of -ey transcription factors

@e=. 4CT7, JL37, C6M8C, S4K'

/SC 6 deri&ed from inner cell mass of lastocyst iPSC6 deri&ed from reprogram

differentiated cell ac- plurip

;


16/21

Potential Uses of Pluripotent Stem Cells

/mryonic Stem

Cell"enetic Manipulation

gain6of6functionloss6of6function

De&elopmental

#iology

Mesoderm

/ctoderm/ndoderm

Cell Replace

TherapyDrug Disco&ery

>


17/21

0o+ do you Differentiate Pluripotent Stem Cells

Undifferentiated

/S cells

Analye Differentiated Cells

Cells differentiated

as emryonic odies


on stromal cells


on e=tracellular matri= pr

111!nitiate Differentiation$6L!3, 6emryonic feeders

B


18/21

Patient Specific Approaches for Using DMD6hiPS

4tain patient cells De&elop iPSCs

Transplant corrected muscle cells

De&elop s-e

muscle proge

genetically m

to partially re

functionDe&elop a Pre6Clinical Screening

Tool using Patient Specific Cells

S C ll d D h M l D h


19/21

Stem Cells and Duchenne Muscular Dystrophy

? Dystrophic muscles are highly s

contraction6induced in(ury due t

dystrophin.? This impairs the protecti&e shea

myofiers @the sarcolemma, le

myofier necrosis and acti&atio

satellite cells.? Acti&ated satellite cells di&ide

gi&ing rise to one satellite cell, aproliferating daughter cell that g

myolasts.? The myolasts migrate to the s

differentiate into myocytes, alig

the damaged myofier, repairin

MyofberRegeneration

E

/ h ti f S t llit C ll i DMD


20/21

/=haustion of Satellite Cells in DMD

? 0ea&y urden to repair due to constant

muscle damage

? Lose aility to copy themsel&es

? Lo+ numer affects muscle repair? Damaged muscle fiers are replaced y$

? fat cells @adipose

? scar tissue @firosis

? Muscle can no longer contract effecti&ely

'G

0 C ld St C ll 0 l DMD1


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0o+ Could Stem Cells 0elp DMD1

. Produce ne+ healthy muscle fiers$? "i&e patients normal stem cells to continuously

rene+ muscle

?Correct patients o+n stem cells

ex vivo

andreturn to patient

'. Reduce inflammation or slo+ disease

progression? Secrete )helpful* cyto-ines, proteins, matri=, etc.

5. Personalied genetic medicine

? Screening drugs on patient cells? De&elop patient specific correction strategies

'

Pyle Stem Cell Therapy Part 1

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