How to force epSSCs ➡️ chondroprogenitors to grow MUCH much taller (HIGH IQ THREAD)

[Ibl4meinfras]

Spoiler: What will be covered

What will be covered


#1 mTORC1
#2 Hedgehog (Ihh/Shh)
#3 TGF-b1 / Runx1
#4 Fgfr3i
#5 Sox9 & Wnt Complex
#6 Secret key for everything

Spoiler: MTORC1 pathways

#1 mTORC1

2016 Yan et al.
“Although the mechanistic target of mTORC1 activity is required for chondrocyte growth and proliferation, its inactivation is essential for chondrocyte differentiation”

Regulation of the pool of self-renewing progenitors involves the hedgehog and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. Our findings indicate that a stem cell niche exists in the chondrocyte growth plate which provides a continuous supply of chondrocytes.


mTORC1 ON = proliferation
mTORC1 OFF = differentiation


Synergizes with Hedgehog to renew chondroprogenitors
and maximize chondrocyte growth potential


Bonus:
mTORC1 → S6K1 → Gli2 phosphorylation → Gli2 release from SuFu →
Gli2 nuclear translocation ↑ → PTHrP transcription


Very pro-growth protein even ignoring the PTHrP factor


Hyperactivation of mTORC1 via TSC1 gene deletion in chondrocytes causes uncoupling of the normal proliferation and differentiation program within the growth plate, resulting in uncontrolled cell proliferation, and blockage of differentiation and chondrodysplasia in mice.

Spoiler: HEDGEHOG

2 Hedgehog (Smo, Shh, Ihh)

Hedgehog-activated PTHrP⁺ chondrocytes formed large, concentric, clonally expanded cell populations within the resting zone (“patched roses”) and generated significantly wider columns of chondrocytes, resulting in hyperplasia of the growth plate.


Directly expands resting zone epSSCs


Administration of SAG also elevated the number of epSSCs. When SAG-containing beads were implanted into the femoral secondary ossification center of 1 leg of rats, this leg was significantly longer 1 month later than the contralateral leg implanted with vehicle-containing beads, an effect that was even more pronounced 2 and 6 months after implantation. We conclude that Ihh signaling activates growth plate epSSCs, which effectively leads to increased longitudinal growth of bones.


Induces symmetrical stem cell division (get 2 instead of 1)

Expands the stem cell pool and widens columns

Spoiler: KARTOGENIN

#3 Kartogenin
Induces


Runx1 — stem cells favors turning into chondrocytes
Smad4/5 — induces Sox9 and collagen (2) for GP growth
TGF-β1 — inhibits differentiation which aids in plate fusion


This signaling cascade effectively commits stem cells into chondroprogenitors.


Our findings demonstrate that KGN treatment significantly increased markers of chondrogenesis, SOX9 and COL2 following 3–10 days of treatment in human CPCs. KGN treatment also resulted in a significant dose-dependent increase in GAG production in CPCs. The same efficacy was not observed in human BM-MSCs; however, KGN significantly reduced mRNA expression of cell hypertrophy markers, COL10 and MMP-13, in BM-MSCs.


Additionally has independent Hedgehog-like effects via Gli1 transcription.


Plan of Action:
[

REMOVED — unsafe experimental drug instructions]


BUT
karto is probably carcinogenic due to being 53% 4-abp
so proceed with high caution

IN TOTAL: plans work but can be very dangerous due to Kartogenin proflericarion via peritostimosis risks, proceed with caution


TAGS:
@182ltn @timfa @Underwear Remover @Stacy destroyer CL



HIGH IQ?

 

[182ltn]

Is the high effort in the room with us?
Did Read good job brev
@Gengar’s Ghost BOTB?

 

[Niebvll]

dnr almost all of it but proliferation and differentiation happen simultaniously in asymmetrical division of epsscs why would they be contraries here?

mTORC1 ON = proliferation
mTORC1 OFF = differentiation

 

[Niebvll]

This is very low effort btw

 

[Niebvll]

dnr almost all of it but proliferation and differentiation happen simultaniously in asymmetrical division of epsscs why would they be contraries here?

@Ibl4meinfras

 

[hyomaxxer]

Spoiler: What will be covered

What will be covered


#1 mTORC1
#2 Hedgehog (Ihh/Shh)
#3 TGF-b1 / Runx1
#4 Fgfr3i
#5 Sox9 & Wnt Complex
#6 Secret key for everything

Spoiler: MTORC1 pathways

#1 mTORC1

2016 Yan et al.
“Although the mechanistic target of mTORC1 activity is required for chondrocyte growth and proliferation, its inactivation is essential for chondrocyte differentiation”

Regulation of the pool of self-renewing progenitors involves the hedgehog and mammalian target of rapamycin complex 1 (mTORC1) signaling pathways. Our findings indicate that a stem cell niche exists in the chondrocyte growth plate which provides a continuous supply of chondrocytes.


mTORC1 ON = proliferation
mTORC1 OFF = differentiation


Synergizes with Hedgehog to renew chondroprogenitors
and maximize chondrocyte growth potential


Bonus:
mTORC1 → S6K1 → Gli2 phosphorylation → Gli2 release from SuFu →
Gli2 nuclear translocation ↑ → PTHrP transcription


Very pro-growth protein even ignoring the PTHrP factor


Hyperactivation of mTORC1 via TSC1 gene deletion in chondrocytes causes uncoupling of the normal proliferation and differentiation program within the growth plate, resulting in uncontrolled cell proliferation, and blockage of differentiation and chondrodysplasia in mice.

Spoiler: HEDGEHOG

2 Hedgehog (Smo, Shh, Ihh)

Hedgehog-activated PTHrP⁺ chondrocytes formed large, concentric, clonally expanded cell populations within the resting zone (“patched roses”) and generated significantly wider columns of chondrocytes, resulting in hyperplasia of the growth plate.


Directly expands resting zone epSSCs


Administration of SAG also elevated the number of epSSCs. When SAG-containing beads were implanted into the femoral secondary ossification center of 1 leg of rats, this leg was significantly longer 1 month later than the contralateral leg implanted with vehicle-containing beads, an effect that was even more pronounced 2 and 6 months after implantation. We conclude that Ihh signaling activates growth plate epSSCs, which effectively leads to increased longitudinal growth of bones.


Induces symmetrical stem cell division (get 2 instead of 1)

Expands the stem cell pool and widens columns

Spoiler: KARTOGENIN

#3 Kartogenin
Induces


Runx1 — stem cells favors turning into chondrocytes
Smad4/5 — induces Sox9 and collagen (2) for GP growth
TGF-β1 — inhibits differentiation which aids in plate fusion


This signaling cascade effectively commits stem cells into chondroprogenitors.


Our findings demonstrate that KGN treatment significantly increased markers of chondrogenesis, SOX9 and COL2 following 3–10 days of treatment in human CPCs. KGN treatment also resulted in a significant dose-dependent increase in GAG production in CPCs. The same efficacy was not observed in human BM-MSCs; however, KGN significantly reduced mRNA expression of cell hypertrophy markers, COL10 and MMP-13, in BM-MSCs.


Additionally has independent Hedgehog-like effects via Gli1 transcription.


Plan of Action:
[View attachment 5211547REMOVED — unsafe experimental drug instructions]


BUT
karto is probably carcinogenic due to being 53% 4-abp
so proceed with high caution

IN TOTAL: plans work but can be very dangerous due to Kartogenin proflericarion via peritostimosis risks, proceed with caution


TAGS:
@182ltn @timfa @Underwear Remover @Stacy destroyer CL



HIGH IQ?

 

[Abusive]

Only 5 replies? BUMP

 

[Ibl4meinfras]

dnr almost all of it but proliferation and differentiation happen simultaniously in asymmetrical division of epsscs why would they be contraries here?

They aren’t true contraries in a biological sense, they are temporally and spatially separated states even though they originate from the same asymmetric epSSC division. In an asymmetric division, one daughter cell retains a stem or progenitor identity while the other is biased toward differentiation, but those fates are governed by different downstream signaling intensities. mTORC1 being described as “ON = proliferation, OFF = differentiation” is a simplification: high mTORC1 activity supports cell growth, metabolism, and proliferative expansion in the progenitor-like daughter, whereas downregulation of mTORC1 is required later for the differentiating daughter to exit the cell cycle, activate chondrogenic programs, and mature properly. So proliferation and differentiation can emerge from the same division, but they are still functionally opposing cellular programs that must be toggled in sequence and in different daughter cells, which is why they are treated as contraries in pathway discussions even though they are coupled within asymmetric stem cell dynamics.

 

[Niebvll]

They aren’t true contraries in a biological sense, they are temporally and spatially separated states even though they originate from the same asymmetric epSSC division. In an asymmetric division, one daughter cell retains a stem or progenitor identity while the other is biased toward differentiation, but those fates are governed by different downstream signaling intensities. mTORC1 being described as “ON = proliferation, OFF = differentiation” is a simplification: high mTORC1 activity supports cell growth, metabolism, and proliferative expansion in the progenitor-like daughter, whereas downregulation of mTORC1 is required later for the differentiating daughter to exit the cell cycle, activate chondrogenic programs, and mature properly. So proliferation and differentiation can emerge from the same division, but they are still functionally opposing cellular programs that must be toggled in sequence and in different daughter cells, which is why they are treated as contraries in pathway discussions even though they are coupled within asymmetric stem cell dynamics.

Bro really needed an ai to answer

 

[Bsd]

kinda water im ngl mirin effort tho