Arjun Jain

PhDing @RetroBio_ | penn 22

[zack chiang @z_chiang]

was initially quite skeptical of "industry PhDs" but Arjun is one of the most prolific scientists I've worked with

many people assume that iPSC therapies are just for replacing lost cells, but here we show we can rejuvenate the system that forms ~80% of human cells!

[zack chiang @z_chiang]

call me, beep me if you wanna reach me

[Arjun Jain @arjunjain527]

(13/13)
Overall, this research supports a path toward renewable, engineerable HSC grafts that combine long-term function with youthful molecular features.

Huge thanks to everyone at @RetroBio_ and to our collaborators at MCRI who made this possible, especially my mentors Anastasia Shindyapina and Swathi Karthikeyan, as well as @AlexandreTrapp, @jnearestn, @z_chiang, and many others at Retro.

Very excited to finally share it and to see where this takes us next.

[Arjun Jain @arjunjain527]

(12/13)
Reprogramming to iPSCs is known to reset many molecular features of aging. What was unknown was whether that youth could survive differentiation into HSCs and the enormous proliferative stress of rebuilding a blood system twice.

Here, it did.

[Arjun Jain @arjunjain527]

(11/13)
Why might this matter?

HSC aging is associated with weaker regeneration, immune aging, biased blood production, and poorer transplant outcomes. A youthful and functional HSC pool could potentially provide greater long-term regenerative reserve (although that remains to be tested clinically).

[Arjun Jain @arjunjain527]

(10/13)
And there was more in the DNA methylation data:

While age-associated methylation patterns remained reset even after transplants, HSC identity-associated methylation patterns of engrafted human blood shifted towards that of primary adult HSCs.

In other words, adult HSC identity and epigenetic aging could be separated.

[Arjun Jain @arjunjain527]

(8/13)
Serial transplantation asks whether stem cells can rebuild one blood system, make more stem cells (self-renew), and then rebuild another. A blood transfusion supplies mature cells for a limited time, but a true HSC graft establishes the source that continuously produces new blood and immune cells.

Together, these grafts persisted through nearly 10 months of continuous blood production in vivo.

[Arjun Jain @arjunjain527]

(9/13)
Remarkably, they also stayed molecularly young (measured by DNA methylation/epigenetic clocks):

Average epigenetic age was:
~0.6 years before transplant
~1.7 years after primary engraftment
~5.3 years after secondary engraftment
(even when the original donor was 60 years old).

Our iPSC-derived HSCs also had longer telomeres than adult donor HSCs (~11.5 versus ~8.4 kb) and far fewer critically short telomeres (~1.3% versus ~10.6%).

[Arjun Jain @arjunjain527]

(7/13)
Then came one of the field’s hardest tests: serial transplantation.

For 3 of the donors, we transferred bone marrow from primary recipients into new mice for another 5 months.

18/23 secondary recipients had human blood reconstitution in the bone marrow (up to 85% of the marrow was human!) again while producing balanced blood lineages.

[Arjun Jain @arjunjain527]

(5/13)
The problem: making true HSCs from iPSCs has historically been very difficult. Cells can look like HSCs in a dish, but fail to transplant and reconstitute blood in mice models.

However, a recent breakthrough from our collaborators at MCRI, may have changed this: https://t.co/esYjVXoEJf

[Arjun Jain @arjunjain527]

(6/13)
Using their differentiation protocol, we generated iPSC-derived HSCs from six adult donors, ranging from 18 to 60 years old, and transplanted these into immunodeficient mice to test their function.

After 5 months, 94/106 transplanted mice had substantial human blood reconstitution. The grafts produced erythroid, myeloid, B cell, and T/NK cell compartments while self-renewing in the bone marrow (they worked!).

[Arjun Jain @arjunjain527]

(4/13)
This is why induced pluripotent stem cells, or iPSCs, are so exciting.

iPSCs are adult cells ‘reprogrammed’ into a renewable, pluripotent state. They can be expanded, edited, and differentiated into many cell types, potentially providing an abundant source of HSC grafts.

[Arjun Jain @arjunjain527]

(2/13)
Hematopoietic stem cells (HSCs) sit at the root of the entire blood system.

They self-renew in bone marrow and continuously make red blood cells, platelets, and immune cells throughout life.

A successful HSC transplant can rebuild a patient’s blood and immune system, and this is the standard of care for some blood cancers and inherited blood disorders.

[Arjun Jain @arjunjain527]

(3/13)
But today’s HSC transplants have major limitations:
Matched donors can be difficult to find.
Older donor cells generally perform less well, as HSC function declines with age.
Donor grafts can attack the recipient, and the conditioning used to make space in bone marrow can be highly toxic.

[Arjun Jain @arjunjain527]

I’m excited to share the first paper from my PhD research at @RetroBio_ (and my first paper as first author) - now on bioRxiv!

Can we take adult human cells, turn them into blood-forming stem cells, and build a new blood system that is both functional and molecularly young?

Our preprint: https://t.co/1Z1w0l3Kag

[Ocampo Lab @OcampoLab]

Excited to share our new publication! We previously showed that age reversal can be achieved using transcription factor-based reprogramming. Now, we demonstrate that it can also be done with chemical cocktails to achieve lifespan extension!
https://t.co/hxgIhAOW0U

[Arjun Jain @arjunjain527]

@basilp_nft @davidasinclair @lifebiosciences 12% increase in overall lifespan

[Arjun Jain @arjunjain527]

cool to see @davidasinclair share the news article i wrote with some @RetroBio_ scientists about recent work @altos_labs. super excited for the future of partial reprogramming therapies - stay tuned

[David Sinclair @davidasinclair]

NEW PAPER: Partial reprogramming with virally-delivered OSK genes rejuvenates senescent cells, restores tissue integrity, heals wounds & extends lifespan in mice. Can't wait to see if it works in humans @lifebiosciences 🚀 https://t.co/O7ANo5BDO2

[Arjun Jain @arjunjain527]

@g_vinick_abc @KXAN_News @Austin_Police @KVUE yep, not able to dm you, may require mutual follow - dm me!

[Arjun Jain @arjunjain527]

huge explosion shook buildings across NW austin, unclear where from @KXAN_News @Austin_Police @KVUE

[Arjun Jain @arjunjain527]

just talked to the cops, they confirmed it was an explosion and seem to know where - no other details provided

[Arjun Jain @arjunjain527]

huge explosion shook buildings across NW austin, unclear where from @KXAN_News @Austin_Police @KVUE