Stem cell division

#1

I asked chatGPT for a summary of the processes for stem cell division and thought people might like to see the answer.

Q: what are the stages where a stem cell moves from being quiescent to having a somatic cell that is fully differentiated and a stem cell which is quiescent again and how does this link to hypoxia?

Below is a generic “life-cycle” that many adult tissue stem cells follow—illustrated with haematopoietic, neural and muscle satellite cells—and the oxygen logic that gates each step. Oxygen tensions are expressed as % O₂ in the niche; atmospheric O₂ is ~21 %.

Stage Cell-cycle / fate state Typical O₂ Key HIF / metabolic setting What hypoxia is doing
0 Deep quiescence (G₀) Long-lived, non-cycling stem cell 0.5–3 % HIF-1α (± HIF-2α) stably active; high glycolysis, low mito‐ROS Keeps ROS and replication stress low, up-regulates CXCL12, ID2, PAX7, SOX2, Notch and autophagy genes → preserves stemness and prevents exhaustion (PMC, PubMed, MDPI)
1 “Alert” quiescence (G_Alert) Still G₀ but metabolically primed after injury or IL-6/VEGF signals 2–4 % mTORC1 flickers on, HIF-1α still present but damped Allows rapid ATP & ribosome build-up while the cell remains in place; if signals subside it slides back to stage 0 (Wikipedia)
2 Activation / G₁ entry Stem cell re-enters the cell cycle (G₁-S) 3–5 % HIF-1α starts to fall; MYC, mTORC1 and cyclin-D rise; glycolysis → glycolysis + PPP A slight rise in O₂ (or PHD-mediated HIF degradation) licences CDK activity and chromatin opening needed for S-phase (Cell)
3 Asymmetric division Spindle orients against the O₂ gradient; one SC + one transit cell 3–5 % Polarity genes (NUMB, PAR, aPKC), p53, Notch interact with residual HIF-1α HIF-1α/Notch/p53 axis helps bias fate: the daughter staying closer to the hypoxic niche retains stemness; the one pushed outward becomes progenitor (PMC, PMC)
4 Transit-amplifying (TA) proliferation 3–5 rapid symmetric divisions 5–8 % HIF largely degraded; switch to mixed glycolysis + OXPHOS; rising ROS More O₂ supports mitochondrial ATP needed for bulk biosynthesis; loss of HIF removes block on cell-cycle gene expression (Cell)
5 Early lineage commitment Progenitor expresses tissue TFs (e.g., MyoD, PU.1) 8–12 % TCA-OXPHOS dominant; HIF off; enzymes like KDM/JmjC demethylases now work (they require O₂) Re-oxygenation unmasks oxygen-dependent epigenetic modifiers, enabling lineage-specific gene programmes (EMBO Press)
6 Terminal differentiation Fully specialised somatic cell; cell cycle exit 12–21 % Stable oxidative metabolism; high ROS buffering High O₂ permits functions that need maximal mitochondrial output (muscle contraction, neuronal firing, etc.)
0′ Stem-cell self-renewal The sister that stayed hypoxic migrates back to the niche and re-enters deep quiescence 0.5–3 % HIF-1α fully re-stabilised; mitophagy removes excess mitochondria Restores the long-term stem-cell pool for the next round

Why hypoxia matters at each checkpoint

  1. Maintaining the seed pool Chronic low O₂ stabilises HIF-1α, which in turn enforces expression of niche-retention (CXCL12, SCF) and anti-oxidant genes. Loss of HIF-1α or its partner ID2 in HSCs forces them into cycle and leads to exhaustion. (PMC)
  2. Switching the engine on A partial rise in O₂ (or inflammatory cytokines that activate mTORC1) lowers HIF levels just enough to free cyclin/CDK expression, while still keeping ROS below damaging levels.
  3. Choice of symmetric vs asymmetric division Under modest hypoxia, HIF-1α cooperates with Notch and p53 to polarise NUMB and aPKC, biasing one spindle pole toward the vascular side. That molecular asymmetry predestines one daughter for self-renewal and the other for commitment. (PMC, PMC)
  4. Amplifying without losing genome integrity TA cells leave the most hypoxic zone; the higher O₂ lets mitochondria run harder, but ROS is now high enough to act as a signal for eventual cell-cycle exit. In muscle, prolonged or excessive hypoxia that keeps HIF-2α high stalls this step and impairs regeneration. (Wiley Online Library)
  5. Locking in fate Many histone and DNA demethylases need molecular oxygen; re-oxygenation therefore “opens” chromatin at lineage loci and closes stemness loci. Neural stem cells, for example, begin differentiating rapidly when local angiogenesis lifts tissue O₂. (EMBO Press)
  6. Resetting the niche The self-renewed stem cell re-enters the low-O₂ pocket, re-accumulates HIF-1α, purges surplus mitochondria and returns to the long-term, damage-resistant quiescent state.

Tissue examples

  • **Haematopoietic stem cells (HSCs) ** – reside at 1–2 % O₂ in the bone-marrow endosteum; HIF-1α deletion or pharmacological destabilisation drives them out of quiescence and depletes the pool. (PMC)
  • **Muscle satellite cells ** – the sub-laminar niche is ~3 % O₂; hypoxia up-regulates PAX7 and suppresses MyoD, sustaining self-renewal. (PubMed, PMC)
  • **Neural stem cells ** – a hypoxic (<2 % O₂) sub-ventricular zone keeps NSCs dormant; sprouting vessels deliver O₂ bursts that switch on neurogenesis. (EMBO Press)

Take-home

The stem-cell “voyage” from quiescence → activation → asymmetric division → progenitor expansion → terminal differentiation is, in most adult tissues, choreographed by an oxygen gradient. Hypoxia (via HIFs) is the brake that prevents premature cycling and preserves stemness; graded re-oxygenation is the accelerator that lets progeny proliferate and finally lock into a differentiated fate, while the original stem-cell half retreats back into hypoxic safety to begin the cycle anew.

1 Like
Ora Biomedical Million Molecule Challenge Results
#2

This has a number of my favourite things in it (HIF 1 alpha, acetyl-CoA etc etc) I had a discussion with the hacking aging group about oxygen, which people might find interesting.

Summary from chatGPT

Video in a nutshell

  • What it is: a 90-minute Anti-Aging Reading Group session streamed on 30 March 2024, moderated by longevity enthusiast John Hemming. The talk is entitled “Discussion about Oxygen, Hypoxia and Hyperoxia” and it mixes a prepared presentation with open Q-and-A from the Zoom audience. (Rapamycin Longevity News)

1. The physiology primer – oxygen at three levels

  • Normoxia (≈ 21 % O₂), hypoxia (< ≈ 18 %), hyperoxia (> ≈ 30 %) set very different red-ox and gene-expression landscapes in the body.
  • Key molecular “oxygen gauges” highlighted in the video are HIF-1α (activated when O₂ falls), NRF2 (up-regulated by mild oxidant stress), and NF-κB (inflammatory signal that rises when oxidant stress is too high).
  • Hemming clarifies that hypoxia in this context is moderate, transient tissue under-oxygenation—nothing close to the medical emergency of anoxia. (Wikipedia, Wikipedia)

2. The “Normobaric Oxygen Paradox” & “Hyperoxic-Hypoxic Paradox”

  • Counter-intuitively, a brief spell of high inspired O₂ (e.g., 60 % for 15-30 min) followed by a return to room air can mimic hypoxia at the cellular level.
  • The drop in dissolved-oxygen tension during that return to normoxia stabilises HIF-1α and spikes erythropoietin (EPO), angiogenic factors, and autophagy genes—without the discomfort of true low-oxygen breathing.
  • Hemming walks through several papers and derives a simple “challenge figure” (Δ FiO₂ × time) to predict when the HIF response switches to a pro-inflammatory NF-κB response. (johnhemming.blogspot.com)

3. Potential benefits of cycling O₂

Pathway turned on Claimed downstream benefit (human or animal data)
HIF-1α & EPO ↑ red-cell mass, ↑ exercise tolerance
NRF2 ↑ endogenous antioxidant capacity, ↓ ROS damage
Stem-cell signals ↑ proliferation & wound-healing, possible telomere lengthening (pilot HBOT data)

Hemming stresses that most evidence is pre-clinical or in small human trials, but the convergence of results across intermittent hypoxia, intermittent hyperoxia and exercise is “too interesting to ignore.” (johnhemming.blogspot.com)

4. How people are already using it

  • Home oxygen concentrator + switch-valve rigs to alternate 60 % O₂ and room air while working at a desk.
  • LiveO2™ and similar EWOT systems that oscillate between hyperoxic and mild hypoxic gas during stationary cycling.
  • Breath-hold / CO₂-tolerance drills and altitude tents for a purer hypoxic stimulus.
    Forum participants share n = 1 experiences and papers on intermittent hypoxia in sports, Parkinson’s disease and cognition. (Rapamycin Longevity News)

5. Risks & “U-shaped” reality check

  • Hyperoxia > 0.6 bar pO₂ for hours markedly raises lung and CNS oxygen-toxicity risk; mortality increases have been documented in ventilated ICU patients given FiO₂ > 60 % for prolonged periods.
  • Severe hypoxia (< 10 % O₂ for minutes) can cause neuronal death.
  • The video repeatedly underscores the need to stay in the “goldilocks” zone—moderate intensity, short duration, intermittent exposure, ample recovery. (Wikipedia, johnhemming.blogspot.com)

6. Suggested practical template (not medical advice)

Step Typical setting mentioned Rationale
1. Warm-up 3-5 min normal breathing Baseline saturation
2. Hyperoxic pulse 60–85 % O₂ for 10-20 min (mask) Create ROS burst & antioxidant priming
3. Rapid switch to normoxia Room air for ≥ 5 min HIF-1α stabilisation (per NOP)
4. Optional low-O₂ bout 14–16 % O₂ for 5 min or controlled breath-hold Additional HIF/VEGF if tolerated
5. Cool-down Light movement, normal air Re-equilibrate, avoid rebound dizziness

Hemming cautions viewers to monitor SpO₂, limit total “challenge figure” and avoid unsupervised extremes, especially if they have cardiovascular, pulmonary or seizure risk. (johnhemming.blogspot.com)

7. Audience Q-and-A highlights

  • Breath-hold training: one attendee reports dropping SpO₂ to the low-60 % range after 15 weeks of practice; Hemming notes this is beyond what he considers necessary.
  • CPAP vs intermittent hypoxia: mild sleep-apnea desaturations are not the same stimulus; fragmented sleep negates gains.
  • Drug mimetics (e.g., Roxadustat): can emulate HIF activation but still under study for safety in healthy people.
  • Future directions: more RCTs on intermittent hypoxic-hyperoxic therapy (IHHT) for neuro-degeneration and metabolic health are ongoing. (Rapamycin Longevity News)

Bottom line:
The session argues that smart, time-limited swings in oxygen availability may offer a low-tech way to tap repair pathways normally triggered by hill running, diving, or high-altitude living—provided you respect the narrow line between hormesis and harm.

Transcript from you tube tided up by chatGPT

Tidied Transcript (filler words, false starts and time-stamps removed; punctuation and paragraph breaks added for readability)

Host:
Shall I share my screen? Yes? All right, let’s get started.

John Heming:
Today we’re talking about oxygen. One difficulty when reading the literature is that the same word often means different things. Everybody knows air pressure drops with altitude: at sea-level it’s 1.013 × 10⁵ N m⁻², or 760 mm Hg.

For any gas we care about its partial pressure—the fraction of total pressure attributable to that gas. Because we’re focused on oxygen, we also need a few terms:

Term Meaning
Hyperoxia Higher-than-normal oxygen level
Hypoxia Lower-than-normal oxygen level
Normoxia Normal oxygen level
Hyperbaric / Normobaric / Hypobaric High / normal / low total pressure

Those last three give rise to the “normobaric oxygen paradox”: a hypoxic-type cellular response provoked by briefly raising, then returning, the partial pressure of oxygen at normal atmospheric pressure. I’ll reference papers on that later.

The normal atmosphere is ~21 % O₂, 78 % N₂, ~1 % Ar, a trace of CO₂, plus variable water vapour. Geological evidence suggests O₂ was once closer to 40 %. At sea level the O₂ partial pressure is ~160 mm Hg and oxygen’s solubility in water is low—but high enough that, under several atmospheres of pressure, researchers once kept a pig alive with oxygenated saline without haemoglobin.

Moving from lungs to tissues:

  • lungs: ~160 mm Hg
  • haemoglobin release: 20–40 mm Hg needed
  • dissolved O₂ in plasma at the mitochondria: only a few mm Hg

Two ways to raise pO₂: increase fraction of O₂ (e.g. 40 % O₂ at 1 atm) or increase total pressure (e.g. 21 % O₂ at 2 atm). Hyperbaric oxygen therapy (HBOT) often combines both.

Sustained hypoxia is toxic (e.g. birth asphyxia). Sustained hyperoxia is also toxic—excess reactive oxygen species (ROS). At altitude (Everest ~0.3 atm) pO₂ is ~55 mm Hg; under the sea, every 10 m adds ~1 atm. Divers try to keep inspired pO₂ below ~1.5 atm to avoid oxygen toxicity, sometimes by breathing “trimix” with only 10 % O₂.

A few curiosities:

  • Naked mole-rats and bowhead whales live in chronically hypoxic niches and have exceptional longevity.
  • Mammalian reproduction begins in a hypoxic oviduct (~40 mm Hg); early embryonic stem-cell niches are also hypoxic.
  • Low O₂ diverts metabolism away from oxidative phosphorylation toward lactate—but there is also a non-canonical TCA cycle that shuttles citrate out of mitochondria via SLC25A1, supplying cytosolic acetyl-CoA for histone acetylation and stem-cell maintenance.

Three stress-responsive transcription factors form a rough graduated defence:

Oxygen/ROS stress Primary factor “Role”
Mild HIF-1α Builders – angiogenesis, erythropoiesis, stem-cell activation
Moderate NRF2 Fire-fighters – antioxidant enzyme induction
Severe NF-κB Army – pro-inflammatory, innate immune activation

HBOT clearly triggers benefits—improved telomere length, wound healing, etc.—but evidence suggests many gains come not from the high pO₂ itself but from the drop back to normal: the normobaric oxygen paradox.

Practical demonstration (John shows equipment):

  • A domestic oxygen concentrator delivers ~95 % O₂; once mixed with room air you inhale ~60 % O₂. Wearing the mask for ~20 min then removing it should trigger a HIF response without needing a hyperbaric chamber.
  • Conversely, a small electrolyser can supply ~2–6 % H₂ for inhalation; molecular hydrogen scavenges the highly reactive •OH radical and may blunt oxidative damage. (Intestinal bacteria already generate H₂—major component of flatus!)

Discussion highlights

  • Hypoxia vs stem-cell potency – several papers show that low O₂ helps keep stem cells pluripotent; differentiation involves a metabolic shift.
  • Exercise is a simpler, well-proven HIF stimulus—localized hypoxia during effort, followed by re-oxygenation.
  • Too much oxygen for too long is harmful; the art is a short, controlled pulse.
  • Biomarkers: John monitors weekly CRP (<0.15 mg L⁻¹), ferritin (reduced from 300–400 µg L⁻¹ to ~80), CGM glucose, etc. He layers multiple mild AMPK activators, rapamycin intermittently, and other interventions rather than betting on a single “silver bullet.”
  • The group debates whether ageing is programmed or mainly an accumulation of failures (e.g. long-gene under-expression, mitochondrial heteroplasmy). Agreement: multiple hallmarks interact; no single therapy will suffice.
  • Policy angle: in the US a new bipartisan Congressional Longevity Science Caucus could accelerate translational work; comparable All-Party Parliamentary Groups exist in the UK.

Next steps

  • Sam will present next week (1 pm Sunday).
  • John will upload this recording to his YouTube channel.
  • Attendees are invited to the June 22 longevity conference in Chicago, featuring Shelly Buffenstein on naked-mole-rat biology.

(End of tidied transcript)

#3

normobaric oxygen paradox:

Today I give me dog a treat,
I gonna stop after I beat.

Not so paradoxical. Warm shower before sleep is similar. The return to normal works somewhat like cooling to below normal.