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TISSUE RENEWAL,

REGENERATION AND REPAIR


Dr. Upik A. Miskad, PhD, SpPA
Out line

1. Control of normal Cell Population


 Tissue proliperative activity
 Stem cell
2. Cell cycle
 Growth factor and signaling
3. Tissue Regeneration
4. ECM and Cell-ECM interaction
5. Healing by Repair, Scar Formation and
Fibrosis
Introduction healing Process

 Injury to cells n tissues induce a series of


events that contain damage and healing
process.

 The healing process separated into;


 Regeneration
 Repair
Introduction healing Process

 1. Regeneration
 Proliferation of cells and tissues to replace lost structure
 Replacement of injured cells by cells of the same type
 Some times no residual trace.

 2. Repair
 Combination of regeneration and scar formation
 Replacement by connective tissue
 Leave permanent scar.
FIBROSIS describe extensive deposition of Collagen.
Introduction healing Process

 Scar formation is the predominant when


the extracellular matrix (ECM) framework is
damaged by severe injury .

 Chronic inflammation stimulates scar


formation because of local production of
growth factors and cytokines that promote
fibroblast proliferation and collagen
synthesis. (Fibrosis).
Introduction healing Process
 ECM components are essential for wound
healing because provide the framework for
cell migration, maintain the correct cell
polarity for the re-assembly of multilayer
structures and participate in the formation
of new blood vessels (angiogenesis)

 Cells in the ECM (fibroblasts, macrophages,


and other cell types) produce growth
factors, cytokines, and chemokines that are
critical for regeneration and repair.
Overview of healing responses after injury. Healing after acute injury can
occur by regeneration that restores normal tissue structure or by repair with
scar formation. Healing in chronic injury involves scar formation and
fibrosis .
 REGENERASI
Proliferasi sel atau
jaringan untuk
menggantikan struktur
yang hilang

 REPAIR /
PERBAIKAN
Kombinasi regenerasi
& pembentukan skar.
TISSUE RENEWAL,
REGENERATION AND REPAIR

 Control of Normal Cell Proliferation and


Tissue Growth.
 Cell Cycle and the Regulation of Cell
Replication.
 Mechanisms of Tissue and Organ
Regeneration.
Control of normal cell
proliferation and tissue growth
 Jumlah populasi sel
pada jaringan
ditentukan oleh :
 Proliferasi
 Diferensiasi
 Apoptosis

Proliferasi bisa dipicu


kondisi fisiologis
maupun patologis
Tissue Proliferative Activity
1. Continuosly dividing cells/
labile cells
• Proliferate throughout life, replacing those
that are destroyed.
• These tissues include
– surface epithelia, such as stratified squamous
epithelia of the skin, oral cavity, vagina, and cervix;
– the lining mucosa of all the excretory ducts of the
glands of the body (e.g., salivary glands, pancreas,
biliary tract);
– the columnar epithelium of the GI tract and uterus;
– the transitional epithelium of the urinary tract, and
cells of the bone marrow and hematopoietic tissues.

Most of them derived from ADULT STEM CELLS
2. Quiescent/ Stable cells
• have a low level of replication; can undergo rapid division
in response to stimuli and are thus capable of
reconstituting the tissue of origin.
• Consist of:
– the parenchymal cells of liver, kidneys, and pancreas
– mesenchymal cells such as fibroblasts and smooth muscle,
chondrocytes, and osteocytes ;
– vascular endothelial cells; and
– lymphocytes and other leukocytes.

– EXAMPLE: the ability of the liver to regenerate after partial


hepatectomy and after acute chemical injury.
– Fibroblasts in particular can proliferate extensively, as in
healing processes and fibrosis.
3. Nondividing /permanent
cells
Contain cells that have left the cell cycle and
cannot undergo mitotic division in postnatal
life.
Include: neurons and skeletal and cardiac muscle
cells
If neurons in the central nervous system are destroyed,
the tissue is generally replaced by the glial cells.
Recent research : limited neurogenesis from stem cells
may occur in adult brains.
Cardiac muscle has very limited, if any, regenerative
capacity, and a large injury to the heart muscle, as
may occur in myocardial infarction, is followed by scar
formation.
STEM CELLS
 SEL PUNCA
 Kemampuan “ Renewal “ atau
memperbaharui diri
 Menghasilkan garis keturunan
diferensiasi sel

 Stem cells are characterized by their self-renewal


properties and by their capacity to generate
STEM CELLS

 Research on stem cells is the core of a new field


called regenerative medicine.
 The challenge about cell differentiation,
 The hope that stem cells may one day be used to
repair damaged human tissues, such as heart,
brain, liver, and skeletal muscle.

 STEM CELLS ada 2:


1. Embryonic Stem Cells
2. Adult Stem Cells
STEM CELLS
 Two mechanism of maintenance stem cells: is
achieved by two mechanisms:
 (a) obligatory asymmetric replication, in which with
each stem cell division, one of the daughter cells
retains its self-renewing capacity while the other
enters a differentiation pathway, and
 (b) stochastic differentiation, in which a stem cell
population is maintained by the balance between
stem cell divisions that generate either two self-
renewing stem cells or two cells that will
differentiate.
Figure 3-4 Stem cell generation and differentiation. The zygote, formed by the union of sperm
and egg, divides to form blastocysts, and the inner cell mass of the blastocyst generates the
embryo. The cells of the inner cell mass, known as embryonic stem (ES) cells,
maintained in culture, can be induced to differentiate into cells of multiple lineages. In the
embryo, pluripotent stem cells divide, but the pool of these cells is maintained (see text). As
pluripotent cells differentiate, they give rise to cells with more restricted developmental
capacity, and finally generate stem cells that are committed to specific lineages.
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TOTIPOTENT
• Masa Zygote
• Sel embrional & ekstraembrional ( Plasenta )

PLURIPOTENT
• Bisa menjadi semua sel embrional
• Endo,messo dan ektoderm

MULTIPOTENT
• Terbatas hanya menjadi sel dari satu
garis keturunan tertentu

UNIPOTENT
• Produksi terbatas hanya pada satu tipe
sel saja.
EMBRIONIC STEM CELLS
 Inner cell mass pada Blastocyst
 Kegunaan study tentang ES cells :
1. Mempelajari signal – signal khusus &
tahapan diferensiasi untuk
perkembangan jaringan
2. Mempelajari fakta – fakta biologis gen
& perkembangan penyakit. (Knock out
Mice)
3. Di masa akan datang bisa dipakai untuk
repopulasi jaringan yang rusak
INDUCED PLURIPOTENT STEM CELLS (iPS)

 Sel yang telah terdiferensiasi pada


jaringan dewasa diprogram ulang
agar bersifat PLURIPOTENT,
 Transduksi dengan gen yang
mengkode faktor transkripsi ES
 Oct ¾, Sox2, c-myc, Kfl4, Nanog, Lin28

iPS for REPRODUCTIVE Cloning demonstrated on 1997 by


Cloning Dolly Sheep
ES iPS
THERAPEUTIC CLONING

Figure 3-6 Steps involved in stem cell


therapy, using embryonic stem (ES) cells
or induced pluripotent stem (iPS) cells.
Left side, Therapeutic cloning using ES
cells. The diploid nucleus of an adult cell
from a patient is introduced into an
enucleated oocyte. The oocyte is
activated, and the zygote divides to
become a blastocyst that contains the
donor DNA. The blastocyst is dissociated
to obtain ES cells. Right side, Stem cell
therapy using iPS cells. The cells of a
patient are placed in culture and
transduced with genes encoding
transcription factors, to generate iPS
cells. Both ES and iPS cells are capable
of differentiating into various cell types.
The goal of stem cell therapy is to
repopulate damaged organs of a
patient or to correct a genetic defect,
using the cells of the same patient to
avoid immunological rejection.
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ADULT STEM CELLS

 Stem cell yang ada pada jaringan yang


sudah matur / dewasa
 terus berdiferensiasi c/. Adult SC pada
Sumsum tulang, kulit,otak, mukosa GIT
 Ada hepar, pankreas, jaringan lemak, tapi
dalam keadaan inaktif pada kondisi normal.
STEM CELL pada HOMEOSTASIS JARINGAN
 SUMSUM TULANG :
HEMATOPOIETIC STEM CELLS
 Menghasilkan semua turunan sel – sel darah
 Bisa didaptkan langsung dari sumsum tulang,
darah tali pusat, darah perifer yang menerima
sitokin yang menggerakkan HSC’s
MARROW STROMAL CELLS
 Multipotent
 Menghasilkan chondrocyte, osteoblast,
adipocyte, myoblast prekursor sel
endothelial
 HEPAR
 stem cell berada dalam kanal “Herring “
(pertemuan ductus billiaris & parenkim hati)
 Dpt berkembang menjadi prekursor = sel
oval, & kemudian berdiferensiasi menjadi sel
hepatosit dan sel biliaris
 Berperan sebagai cadangan & aktif hanya
bila terjadi bloking proliferasi hepatosit.
 OTAK
 Neurogenesis dari Neural Stem Cells
(NSCs) terjadi pada manusia dewasa
 NSCs = neural precursor cells
 berdiferensiasi menjadi sel neuron,
astrosit, dan oligodendrosit
 pada subventricular zone (SVZ) & gyrus
dentata pada hippocampus
 KULIT
 Stem cells berada di tonjolan pada folikel
rambut, area interfolikel di permukaan epidermis
& galndula sebacea
 interfolikel stem cells tersebar di epidermis dan
menghasilkan sel epidermis .
 Berperan pada pembentukan kembali sel
epidermis pada penyembuhan luka.
 diaktifasi oleh stimulus dari
Wnt pathway & hambatan
Sinyal BMP system.
 EPITEL INTESTINAL
 stem cell ada dalam kripta usus halus ( di
atas Paneth cell ) atau dasar kripta pada
collon
 beregenerasi dalam kripta 3-5 hari
 Wnt & BMP pathway juga berperan dalam
proliferasi & diferensiasi stem cell
intestinal
 OTOT SKELET & OTOT JANTUNG
 Pada saat terjadi jejas terjadi replikasi sel
satelit
 sel satelit terdiri dari stem cell yang akan
berdiferensiasi menjadi myosit setelah
terjadi jejas
 Delta like ligand → aktifasi Notch
Signaling

Proliferasi sel Satelit
 KOR NEA
 stem cell ( LSCs) ada di pertemuan antara
epitel kornea & kornea
 berfungsi untuk menjaga integritas epitel
terluar kornea agar kornea tetap jernih
Cell cycle and the regulation of
cell replication

 G1 : Presintesis
 S : Sintesis DNA
 G2 : Pre Mitotik
 M : Mitosis
 G0 : Fase Istirahat
G0  Melibatkan protoonkogen & gen yang
dibutuhkan untuk sintesa ribosom &
translasi protein
 Restriction point
G1
 G1/S regulated by Cyclin & CDKs (Cyclin
dependent kinase)
 Check point sebelum replikasi
S
 Check point setelah replikasi
G2  DNA damage / unduplicated DNA
 Monitor sel untuk masuk Mitosis

M
Cell cycle
 Jika adakerusakan DNA → siklus sel
ditunda → DNA Repair
 Jika Kerusakan terlalu berat ;
 Apoptosis
 Senecense ( tidak berreplikasi )

 Check point gagal → Neoplasia


GROWTH FACTOR
 Polipeptida yang mengatur proliferasi sel
 Mempunyai sel target ( multiple / terbatas )
 Berperan untuk survival, lococmotion,
kontraktilitas, diferensiasi & angiogenesis
 GF sebagai Ligand yang berikatan dgn
reseptor spesifik untuk mengirim sinyal ke
sel target
EGF ( Epidermal Growth Factor )
 Reseptor EGFR : EGFR1, ERB B1/EGFR
 Diproduksi oleh keratinosit, makrofag & sel
inflamatori lainnya yang bermigrasi ke area
luka
 Terdistribusi dlm sekresi jaringan & cairan
 Reseptor ERB B2 ( HER 2 atau HER 2/neu ),
ligan utama belum terdeteksi. Overekspresi
HER 2 mengindikasikan adanya kanker
payudara
 Mitogenik thdp sel epitelial, hepatosit,
fibroblas
TGFα ( Transfprming growth
factor α )

 homolog dengan EGF,


 Diproduksi oleh Makrofag, keratinosit,
limfosit,dll
 reseptor EGFR,
 aktivitas biologis nyaris sama dengan EGF
HGF ( Hepatocyte Growth
Factor )

 Diproduksi oleh Fibroblas , sel mesenkim,


sel endotel, sel nonparenkim
 Dalam bentuk pro – HGF, aktivasi oleh”
serine protease”
 Reseptor : c- MET
 Efek mitogenik thdp hepatosit, sel
epitelial.
PDGF ( Pletelet Derived
Growth Factor)

 Diproduksi oleh makrofag aktif, sel endotel,


sel otot polos, & sel tumor
 Tersimpan dalam granul platelet & dilepaskan
oleh platelet yang aktif
 Menyebabkan migrasi & proliferasi fibroblas,
sel otot polos , sel monosit pada area
inflamasi & penyembuhan luka di kulit
VEGF (Vascular Endothelial
Growth Factor )
 Diproduksi oleh banyak tipe sel
 VEGF A, VEGF B, VEGF C, VEGF D & PIGF (
Placental Growth Factor )
 VEGF menginduksi pembentukan pembuluh
darah pada tahap awal ( Vasculogenesis ) dan
berperan pada pertumbuhan pembuluh darah
baru ( angiogenesis ) pada dewasa.
 VEGF merangsang angigenesis pada
inflamasi kronis, penyembuhan luka & pd
tumor
 Mempunyai 3 reseptor ; VEGFR 1, 2, 3
VEGFR 1 : memfasilitasi mobilisasi
endotelial Stem cell & berperan pada
proses inflamasi
VEGFR2 : ada pada sel endothel dan sel
lain, adalah reseptor utama untuk
vasculogenesis & angigenesis
VEGFR3 : berikatan dengan VEGF C & D,
bekerja pd lymphatic endothelial cell (
Lymphangiogenesis )
FGF (Fibroblast Growth Factor)
 acidic FGF ( α FGF/ FGF 1 )
basic FGF ( β FGF / FGF 2 )
 Diproduksi oleh : makrofag,mast cells,
limfosit T, sel endotel,fibroblas
 tranduksi melalui 4 reseptor tirosin kinase
FGFR 1,FGFR2,FGFR3,FGFR4
 FGF1 berikatan pada semua reseptor
 FGF berperan pada respon u/. Penyembuhan
luka,hematopoiesis, angiogenesis, dan
proses lainnya melalui beberapa fungsi :
 Penyembuhan luka : FGF2 & KGF berperan pada
reepitelisasi kulit luka
 Angiogenesis : pembentukan pembuluh darah
baru
 Hematopoiesis : FGF telah terdeteksi pada
proses diferensiasi sel darah & pembentukan
stroma sumsum tulang
 Perkembangan : FGF berperan penting dlm
perkembangan otot skelet & otot jantung,
maturasi paru,& spesifikasi liver dari sel
endodermal
TGFβ
 3 isoform ( TGF β1 , TGF β2, TGF β3 )
 diproduksi oleh : makrofag, trombosit, sel
endotel, limfosit, keratinosit, sel otot polos,
fibroblas
 TGF β disintesa sebagai precursor protein →
dipotong oleh enzym proteolitic →TGF β
aktif
 TGF β yg aktif, berikatan dengan 2 reseptor
permukaan type I & II
 TGF β adl inhibitor pertumbuhan pada
sebagian besar sel epitel
 TGF β bersifat fibrogenic poten →
kemotaksis fibroblas & ↑ produksi kolagen,
fibronectin & Proteoglican
 TGF β mempunyai efek anti inflamasi yang
kuat tapi mungkin ↑ fungsi imun
SITOKIN
 Berfungsi sebagai mediator inflamasi &
respon imune
 Beberapa bisa juga sebagai growth factor,
karena punya aktifitas merangsang
pertumbuhan sel pada berbagai sel
 TNF & IL-1 berperan pd reaksi
penyembuhan luka
 TNF & IL-6 untuk inisiasi regenerasi hati
Mekanisme signaling pd
pertumbuhan sel

Figure 3-8 General patterns of


intercellular signaling demonstrating
autocrine, paracrine, and endocrine
signaling (see text). (Modified from
Lodish H et al [eds]: Molecular Cell
Biology, 3rd ed. New York, WH
Freeman, 1995, p 855. © 1995
by Scientific American Books. Used
with permission of WH Freeman and
Company.)
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SIGNALING MECHANISMS IN CELL
GROWTH
 According to the source of the ligand and the location of its
receptors
• Autocrine signaling: Cells respond to the signaling molecules
that they themselves secrete, thus establishing an autocrine
loop. Tumors frequently overproduce growth factors and their
receptors, thus stimulating their own proliferation through an
autocrine loop.
• Paracrine signaling: One cell type produces the ligand, which
then acts on adjacent target cells that express the
appropriate receptor. The responding cells are in close
proximity to the ligand-producing cell and are generally of a
different type.
• Endocrine signaling: Hormones synthesized by cells of
endocrine organs act on target cells distant from their site of
Receptors and Signal Transduction Pathway

 Ikatan Ligan dgn Reseptor → transduksi


signal → ekspresi gen
 Reseptor biasanya ada di permukaan sel
target,tapi ada juga di dlm sitoplasma &
nukleus
 Satu reseptor bisa mentransduksi
beberapa sinyal pada ikatan ligan.
 JENIS2 RESEPTOR :
 Reseptor dengan aktivitas intrinsik tirosin
kinase
 Reseptor tanpa aktivitas intrinsik tirosin
kinase
 G protein – coupled reseptor
 Steroid hormon reseptor
Figure 3-9 Overview of the main types of cell surface receptors and their principal signal transduction pathways (see text).
Shown are receptors with intrinsic tyrosine kinase activity, seven transmembrane G protein-coupled receptors, and
receptors without intrinsic tyrosine kinase activity. cAMP, cyclic adenosine monophosphate: IP3, inositol triphosphate; JAK,
Janus kinase; MAP kinase, mitogen-activated protein kinase; PI3 kinase, phosphatidylinositol 3-kinase; PKB, protein kinase
B, also known as Akt; PLC-γ, phospholipase C gamma; STATs, signal transducers and activators of transcription.
© 2005 Elsevier
 Steroid Hormon Reseptor
 biasanya terdapat di inti sel
 ligan berdifusi melalui membran sel
dan berikatan dgn reseptor inactive →
aktivasi reseptor → berikatan dengan
faktor transkripsi
Transcription Factor

 Signal transduksi dipakai oleh growth


factor untuk transfer informasi ke inti sel &
memodulasi transkripsi gen melalui
aktifitas faktor transkripsi
 Faktor transkripsi mempunyai bentuk
yang teratur dan terdiri dari domain untuk
DNA binding & u/. Transcription regulation
 Growth factor menginduksi sintesis/ aktifitas
faktor transkripsi
 Modifikasi post translasi Faktor transkripsi :
 Heterodimerisasi
dimerisasi prod c FOS & c JUN → AP-1 →
diaktivasi o/. MAP kinase signaling pathway
 Fosforilasi
STATs pada JAK/STAT pathway
 Release of Inhibition
migrasi ke nukleus, spt pada NF-B
 Release from membranes
o/. Enzym proteolitic cleavage spt pd Notch
reseptor
Mechanism of Tissue and
Organ Regeneration
 Amphibi seperti kadal bisa meregenerasi
ekor, kaki, lensa dll jika organ tsb rusak.
 kemampuan regenerasi jaringan ini tidak
ada pada mamalia o.k tidak ada “ Blastema “/
Source cells
 pd mamalia Wnt/β catenin pathway
memodulasi fungsi stem cell dalam
ep.intestinal, sumsum tulang, dan otot &
berperan pd regenerasi hepar & proliferasi
sel oval .
Liver Regeneration
 Hepar manusia mampu berregenerasi
contohnya setelah partial hepatectomy.
 Reseksi hampir 60% pd donor → dlm 1
bulan bisa regenerasi sampai 2x lipat.
 Pertumbuhan jaringan o.k pembesaran
lobus stelah operasi = hiperplasia
kompensatoris
 proliferasi hepatosit dipicu oleh sitokin dan
growth factor
 Replikasi hepatocyte juga tergantung pd
efek parakrin HGF & IL-6 yang diproduksi
oleh sel nonparenkim hati
 hepatosit bisa masuk ke siklus sel di
mediasi oleh TNF & IL-6
 dengan bantuan growth factor a.l;
HGF,TGFα,HB-EGF, hepatosit masuk
siklus sel → replikasi DNA
Figure 3-11 Liver regeneration after partial hepatectomy. A, The lobes of the liver of a rat (M, median; RL and LL, right and left lateral lobes; C, caudate lobe). Partial
hepatectomy removes two thirds of the liver (median and left lateral lobes). After 3 weeks the right lateral and caudate lobes enlarge to reach a mass equivalent to that of
the original liver without regrowth of the median and left lateral lobes. B, Entry and progression of hepatocytes in the cell cycle (see text for details). C, Regeneration of
the human liver in living-donor transplantation. Computed tomography scans of the donor liver in living-donor hepatic transplantation. Upper panel is a scan of the liver of
the donor before the operation. The right lobe, to be used as a transplant, is outlined. Lower panel is a scan of the liver 1 week after performance of partial hepatectomy.
Note the great enlargement of the left lobe (outlined in the panel) without regrowth of the right lobe. (A, From Goss RJ: Regeneration versus repair. In Cohen IK et al
[eds]: Wound Healing. Biochemical and Clinical Aspects. Philadelphia, WB Saunders, 1992, pp 20-39; C, courtesy of R. Troisi, MD, Ghent University, Ghent, Belgium;
reproduced in part from Fausto N: Liver regeneration. In Arias I, et al: The Liver: Biology and Pathobiology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2001.)
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