This document summarizes a journal club discussion on cell cycle kinetics of hematopoietic stem cells. It discusses the concepts of quiescence and dormancy in stem cells and compares the conventional and dormancy models of hematopoiesis. It reviews different methods for studying stem cell quiescence like BrdU, H2B, and CFSE labeling and their advantages and disadvantages. It highlights a recent study using CFSE labeling that challenges the notion that stem cell function is directly associated with quiescence and that long-term repopulating stem cells are permanently split into cycling and dormant populations. It proposes hypothetical dynamic models of steady state hematopoiesis where the quiescent and cycling fractions of stem cells fluctu

1. Revised: Cell cycle kinetics of hematopoietic stem cells Alexey Bersenev Journal Club May 12, 2011

3. Cycling cell fate decisions: quiescence senescence apoptosis proliferation self-renewal differentiation/ maturation dormancy?

5. active dormant feedback loop long-term progenitors short-term HSC quiescence self-renewal Conventional model Dormancy model mature blood cells LSK/34-/Flk2-/48-/150+ Dormancy model of hematopoiesis:

6. Dormant versus active HSC Andreas Trumpp 2008-2009, Linheng Li, Hans Clevers 2010 characteristics dormant HSC active HSC synonyms quiescent primed, self-renewing phenotype LSK/CD34-/Flk2-/CD48-/CD150+ % in HSC pool ~ 15% ~ 85% quiescence +++ + self-renewal rate +++ + proliferation + +++ replication machinery off on metabolism hibernation/hypoxia active function repair in emergency normal blood turnover niche endosteal vascular signaling Wnt-off/ BMP-on Wnt-on/ BMP-off activation signals active HSC depletion/ INF-α progenitors delpetion feedback loop +++ +

15. Challenge the dormancy model: Long-term repopulation HSC are not necessarily permanently split into subpopulations with different cycling kinetics

16. Hypothetical models of steady state hematopoiesis turnover rate: HSC divide every 17.8 days (BrdU/ biotin) aHSC divide every 9-36 days (H2B) dHSC divide every 56-145d HSC divide every 39 days – 18 divisions during lifetime (CFSE)

17. “ Dynamic repetition” model - Some HSC dominate blood formation for a time, subsequently enter a quiescent state in which other HSC increase hematopoietic contribution, and get reactivated again – repetitive cycles “ dynamic equilibrium” between quiescent fraction and cycling fraction within the HSC population For the first time was proposed by Ingmar Glauche et al. Stem cell proliferation and quiescence--two sides of the same coin . PLoS Comput Biol. 2009 Jul;5(7):e1000447 2009 Glauche concept: HSC flexibly and reversibly adapt their cycling state according to systemic needs