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Some Elaine Fuchs info


#1

(Jan. 25, 2008) — Like fine china and crystal, which tend to be used sparingly, stem cells divide infrequently. It was thought they did so to protect themselves from unnecessary wear and tear. But now new research from Rockefeller University has unveiled the protein that puts the brakes on stem cell division and shows that stem cells may not need such guarded protection to maintain their potency.

This research, to be published in the January 25 issue of Cell, raises questions about what stem cells need in order to maintain their ability to regenerate tissue. It may also be key in developing new treatments for thinning hair.
The impetus for the work began five years ago when Elaine Fuchs, head of the Laboratory of Mammalian Cell Biology and Development, and several researchers in her lab discovered that the protein NFATc1 was one of only a few that are highly expressed within the stem cell compartment of the hair follicle. Clinical research, meanwhile, showed that a particular immunosuppressant that inhibits NFATc1, a drug called cyclosporine A, has a rather unsightly side effect: excessive hair growth.
Fuchs and Valerie Horsley, a postdoc in her lab, realized that there was a connection between the drug’s side effect and the abundance of NFATc1 within the hair follicle’s stem cell compartment — the bulge. The mice they treated with the drug grew fur at a much faster rate than mice they did not treat. The researchers then showed that this excessive hair growth was due to increased stem cell activity within the bulge, a process that cranked up the production of hair. Specifically, the hair cycle shifted gears from its resting phase, when stem cells slumber, to its growth phase, when stem cells proliferate.
To maintain their multipotent properties, though, it appears that these stem cells hardly needed much “rest” at all. These findings came as a surprise to the researchers, who, like their colleagues, had believed that stem cells proliferating infrequently protected them from depletion or mutations that would lead to hair loss. “It seems like the resting phase isn’t as necessary as was once thought,” says Horsley. “Even though these stem cells are highly proliferative, they still maintain their stem cell character.”
Using genetically engineered mice bred by colleagues at Harvard Medical School, Horsley and Fuchs then further explored what happens when skin stem cells lack NFATc1. They found that these mice looked exactly like the hairy mice that were treated with cyclosporine A: The loss of NFATc1 didn’t stop the hair cycle, but rather shortened the resting phase and prompted precocious entry to the growth state.
In probing the underlying mechanisms mediating this process, Horsley and Fuchs discovered that NFATc1, a transcription factor, blocks the expression of a gene that provides the cell cycle with “go ahead” signals at certain checkpoints. By blocking these signals, NFATc1 prevents the stem cells from dividing, preventing unnecessary wear and tear. These same cells, if treated with cyclosporine A, show a rapid loss of the transcription factor, an effect that turns the light green at these checkpoints.
For those with thinning hair, this research may hold promise. As people age, the resting phase of the hair cycle gets longer and longer such that the stem cells proliferate less frequently and hair does not grow at the rate it once did. “If we could use a local and more specific inhibitor of NFATc1 than cyclosporine A to stimulate these stem cells, which are just sitting there during an extended resting phase, we might be able to promote new hair growth,” says Fuchs, who is Rebecca C. Lancefield Professor at Rockefeller and an investigator at the Howard Hughes Medical Institute. “In a sense, by blocking NFATc1 activity in our older mice, their hair follicles were brought back to what appeared to be a more youthful state.”
So far, these proliferating stem cells lacking NFATc1 have not led to increased tumor formation, which is often a dangerous byproduct of triggering stem cells into action. “This is the first case where we have been able to activate the hair cycle without accompanying signs of tumorigenesis,” says Fuchs. “If we can control the activation process of follicle stem cells without promoting tumorigenesis, then this would be a big move in the right direction.”
This research was supported in part by the National Institutes of Health, American Society for Clinical Investigation and the Damon Runyon Cancer Research Foundation. Fuchs is a faculty member in Rockefeller’s Center for Clinical and Translational Science, which is supported by the NIH’s Clinical and Translational Science Award (CTSA) program.

Article 2

Hair Formation, Skin Stem Cells And BMP Signaling

The February 15th cover story of G&D reports on the recent discovery by Dr. Elaine Fuchs and colleagues at the Rockefeller University that BMP signaling in dermal papilla cells is important for hair follicle formation.

The dermal papilla (DP) is a small cluster of mesenchymal cells that exist at the base of the hair follicle, and instruct nearby epithelial stem cells to induce hair follicle growth. But because DP cells are so few in number, and loose their hair-inducing potential in culture, the details of this molecular conversation have remained elusive.

Dr. Fuchs’ team developed a clever genetic strategy to delete specific genes of interest in DP cells, and then graft these genetically engineered cells onto the backs of immunocompromised (and bald) mice, to study the effect of gene deficiency on hair growth.

The researchers found that deletion of the receptor for the bone morphogenetic protein 1a (BMPR1a) in DP cells prevented the formation of hair follicles in engrafted mice. However, if BMPR1a is intact in DP cells, and a bit more BMP protein is added to the cells, then the DP-stem cell cross-talk is prolonged, and recipient mice grow a tuft of hair on their otherwise bald backs.

“Several years ago, we devised a method to purify the cells and characterize the genes expressed by the DP and its neighboring cells that make hair,” says Fuchs. “This gave us clues that BMP signaling might be important in specifying the unique hair-inducing properties of DP cells. We’ve now succeeded in testing this possibility and our findings are important not only for our understanding of the mesenchymal-epithelial crosstalk that is so critical for hair production, but also for developing new and improved methods for stimulating hair growth.”

Interesting.


#2

» (Jan. 25, 2008) — Like fine china and crystal, which tend to be used
» sparingly, stem cells divide infrequently. It was thought they did so to
» protect themselves from unnecessary wear and tear. But now new research
» from Rockefeller University has unveiled the protein that puts the brakes
» on stem cell division and shows that stem cells may not need such guarded
» protection to maintain their potency.
»
» This research, to be published in the January 25 issue of Cell, raises
» questions about what stem cells need in order to maintain their ability to
» regenerate tissue. It may also be key in developing new treatments for
» thinning hair.
» The impetus for the work began five years ago when Elaine Fuchs, head of
» the Laboratory of Mammalian Cell Biology and Development, and several
» researchers in her lab discovered that the protein NFATc1 was one of only a
» few that are highly expressed within the stem cell compartment of the hair
» follicle. Clinical research, meanwhile, showed that a particular
» immunosuppressant that inhibits NFATc1, a drug called cyclosporine A, has a
» rather unsightly side effect: excessive hair growth.
» Fuchs and Valerie Horsley, a postdoc in her lab, realized that there was a
» connection between the drug’s side effect and the abundance of NFATc1
» within the hair follicle’s stem cell compartment — the bulge. The mice they
» treated with the drug grew fur at a much faster rate than mice they did not
» treat. The researchers then showed that this excessive hair growth was due
» to increased stem cell activity within the bulge, a process that cranked up
» the production of hair. Specifically, the hair cycle shifted gears from its
» resting phase, when stem cells slumber, to its growth phase, when stem
» cells proliferate.
» To maintain their multipotent properties, though, it appears that these
» stem cells hardly needed much “rest” at all. These findings came as a
» surprise to the researchers, who, like their colleagues, had believed that
» stem cells proliferating infrequently protected them from depletion or
» mutations that would lead to hair loss. “It seems like the resting phase
» isn’t as necessary as was once thought,” says Horsley. “Even though these
» stem cells are highly proliferative, they still maintain their stem cell
» character.”
» Using genetically engineered mice bred by colleagues at Harvard Medical
» School, Horsley and Fuchs then further explored what happens when skin stem
» cells lack NFATc1. They found that these mice looked exactly like the hairy
» mice that were treated with cyclosporine A: The loss of NFATc1 didn’t stop
» the hair cycle, but rather shortened the resting phase and prompted
» precocious entry to the growth state.
» In probing the underlying mechanisms mediating this process, Horsley and
» Fuchs discovered that NFATc1, a transcription factor, blocks the expression
» of a gene that provides the cell cycle with “go ahead” signals at certain
» checkpoints. By blocking these signals, NFATc1 prevents the stem cells from
» dividing, preventing unnecessary wear and tear. These same cells, if
» treated with cyclosporine A, show a rapid loss of the transcription factor,
» an effect that turns the light green at these checkpoints.
» For those with thinning hair, this research may hold promise. As people
» age, the resting phase of the hair cycle gets longer and longer such that
» the stem cells proliferate less frequently and hair does not grow at the
» rate it once did. “If we could use a local and more specific inhibitor of
» NFATc1 than cyclosporine A to stimulate these stem cells, which are just
» sitting there during an extended resting phase, we might be able to promote
» new hair growth,” says Fuchs, who is Rebecca C. Lancefield Professor at
» Rockefeller and an investigator at the Howard Hughes Medical Institute. “In
» a sense, by blocking NFATc1 activity in our older mice, their hair
» follicles were brought back to what appeared to be a more youthful state.”
» So far, these proliferating stem cells lacking NFATc1 have not led to
» increased tumor formation, which is often a dangerous byproduct of
» triggering stem cells into action. “This is the first case where we have
» been able to activate the hair cycle without accompanying signs of
» tumorigenesis,” says Fuchs. “If we can control the activation process of
» follicle stem cells without promoting tumorigenesis, then this would be a
» big move in the right direction.”
» This research was supported in part by the National Institutes of Health,
» American Society for Clinical Investigation and the Damon Runyon Cancer
» Research Foundation. Fuchs is a faculty member in Rockefeller’s Center for
» Clinical and Translational Science, which is supported by the NIH’s
» Clinical and Translational Science Award (CTSA) program.
»
» Article 2
»
» Hair Formation, Skin Stem Cells And BMP Signaling
»
» The February 15th cover story of G&D reports on the recent discovery by
» Dr. Elaine Fuchs and colleagues at the Rockefeller University that BMP
» signaling in dermal papilla cells is important for hair follicle formation.
»
»
» The dermal papilla (DP) is a small cluster of mesenchymal cells that exist
» at the base of the hair follicle, and instruct nearby epithelial stem cells
» to induce hair follicle growth. But because DP cells are so few in number,
» and loose their hair-inducing potential in culture, the details of this
» molecular conversation have remained elusive.
»
» Dr. Fuchs’ team developed a clever genetic strategy to delete specific
» genes of interest in DP cells, and then graft these genetically engineered
» cells onto the backs of immunocompromised (and bald) mice, to study the
» effect of gene deficiency on hair growth.
»
» The researchers found that deletion of the receptor for the bone
» morphogenetic protein 1a (BMPR1a) in DP cells prevented the formation of
» hair follicles in engrafted mice. However, if BMPR1a is intact in DP cells,
» and a bit more BMP protein is added to the cells, then the DP-stem cell
» cross-talk is prolonged, and recipient mice grow a tuft of hair on their
» otherwise bald backs.
»
» “Several years ago, we devised a method to purify the cells and
» characterize the genes expressed by the DP and its neighboring cells that
» make hair,” says Fuchs. “This gave us clues that BMP signaling might be
» important in specifying the unique hair-inducing properties of DP cells.
» We’ve now succeeded in testing this possibility and our findings are
» important not only for our understanding of the mesenchymal-epithelial
» crosstalk that is so critical for hair production, but also for developing
» new and improved methods for stimulating hair growth.”
»
»
»
» Interesting.

can you give a lay-man’s explanation/summary?


#3

ever since an experiment performed a few years back that moved vellus hairs from bald men to SCID mice with low androgen levels that saw the vellus hairs regenerate to grow as well as donor area hairs…scientists have been wondering what it is that is keeping hairs on men who take finasteride or dutasteride or have been castrated small. What keeps them from growing back in us. Stumptailed macaques on finasteride grow back more hair than people do. When men get on finas, they usually get a little thickening in the crown but just either stop or (usually) slow further loss up in the front. Since we know that vellus hairs can regenerate on the mice without immune systems…its been assumed that some substance or immunological marker is keeping the vellus hairs small by interrupting some signalling that needs to take place. The search has been to find what this substance is. There are various kinds of receptors on hair follicles for substnaces that regulate the haircycle like estrogen receptors, androgen receptors, prostaglandin receptors, and a few more. Various cytokines, peptides, anti-gens have all been suggested to be “the” culprit that keeps hairs on men in the vellus state after they use something like dutasteride, and why men dont get more hair back on these anti-androgens.

Fuchs has apparently found a substance that she feels is keeping the hairs “small”, but there may be more than one. Prostaglandin D2 has been shown by Cotsarialis to be able to keep mice hair from entering a regrowth cycle after their first shed for instance. The substance Fuchs found apparently keeps hairs from getting the “go” signal. Tyrosine kinease inhibitors (there is a new patent out for them with hair growth) have also been suggested to be the substance that keeps hairs from getting the “grow” signalling it needs for stem cells to go to work to initiate a new anagen phase. It was thought for a long time that the excessive collagenous deposition around the follicle physically was blocking it from being able to grow, but one man’s experience with internal spironolactone would seem to invalidate that assertion. I dont have it with me, but a guy who had been bald for 20 years was on internal spironolcatone for 6 years for cirrhosis, and he started to grow back some of his hair all over his head…even in the front. Its a safe bet that after being bald for so long, he’d have alot of collagen “shiny scalp” in the dermal sheath, and crosslinked as all get out, yet the hair apparently after a long while of getting no male hormone (spiro being an androgen receptor blocker) still had the capacity to grow if deprived of male hormone long enough and completely enough. The Dermal Papilla can apparently secrete enzymes (dr. Kevin McElwee wrote this) that can eat through the collagen.

Im not crazy about (even though it would be an elegant solution) trying to regrow long lost hair. I really would rather they could make NEW hair and attempt to block certain genes during its development (or make it out of donor hair cells) that would make the new hair androgen-resistant or have a lower androgen-receptor expression, but will take hair any way I can get it. Someday in the future…they will figure out what makes hair tick and why it gradually goes in response to male hormone, but its probably decades away as the whole thing is so damned complicated. There are 8 sub-stages of anagen, catagen, telogen…the stem cells migrate down from the arrector pilli muscle at the beginning of a new anagen and meet other cells that migrate from the dermal sheath (if I remember correctly) and the DP dives down in the dermis and begins to get fatter, and kertainocyte cells begin to replicate and enlarge…all to cause a new anagen phase. Its very complicated. Nonetheless…the ‘capacity’ is there for the hair to re-grow that is miniaturized all over your scalp. If we could just shut off certain genes topically…it might regrow, or if we could change the genetic expression of the hairs to be like body or beard hairs and LIKE testosterone, it would probably regrow. But those things are way out there in the future. Hair cycles themselves might be chemo-preventive as certain growth factors (mitogens) might need to be periodically shut off for a few weeks to give the area around the follicle a break for them or something. Ive seen that speculated by scientist.

Its another nice find…but one that might be a ways off in terms of having a treatment derived from it, but every little piece of the puzzle gets them closer to finding out what makes hair tick. Hopefully someday, they will be able to give you a topical to use once a week or something and you’d never lose your hair and regrow any that youve lost but its way out there.