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Title: Lifespan Differences in Hematopoietic Stem Cells are Due to Imperfect Repair and Unstable Mean-Reversion}
Article:
Abstract:
The life-long supply of blood cells depends on the long-term function of hematopoietic stem cells( HSCs). HSCs are functionally defined by their multi-potency and self-renewal capacity. Because of their self-renewal capacity, HSCs were thought to have indefinite lifespans. However, there is increasing evidence that genetically identical HSCs differ in lifespan and that the lifespan of a HSC is predetermined and HSC-intrinsic. Lifespan is here defined as the time a HSC gives rise to all mature blood cells. This raises the intriguing question: what controls the lifespan of HSCs within the same animal, exposed to the same environment? We present here a new model based on reliability theory to account for the diversity of lifespans of HSCs. Using clonal repopulation experiments and computational-mathematical modeling, we tested how small-scale, molecular level, failures are dissipated at the HSC population level. We found that the best fit of the experimental data is provided by a model, where the repopulation failure kinetics of each HSC are largely anti-persistent, or mean-reverting, processes. Thus, failure rates repeatedly increase during population-wide division events and are counteracted and decreased by repair processes. In the long-run, a crossover from anti-persistent to persistent behavior occurs. The cross-over is due to a slow increase in the mean failure rate of self-renewal and leads to rapid clonal extinction. This suggests that the repair capacity of HSCs is self-limiting. Furthermore, we show that the lifespan of each HSC depends on the amplitudes and frequencies of fluctuations in the failure rate kinetics. Shorter and longer lived HSCs differ significantly in their pre-programmed ability to dissipate perturbations. A likely interpretation of these findings is that the lifespan of HSCs is determined by preprogrammed differences in repair capacity.
Introduction:
Adult tissue stem cells, such as hematopoietic stem cells( HSCs), are distinguished from mature cells by the ability to generate all mature cell-types of a particular tissue( multi-potency). To generate mature cells, HSCs differentiate into cells of lower potency. The resulting loss of stem cells must be compensated for by self-renewal, i. e. cell divisions which preserve the multi-potential differentiation capacity of the ancestral HSC. The reliability with which HSCs can transfer their identity and maintain self-renewal upon proliferation has been of keen interest to the field[1],[2]. Important questions are: Are daughter HSCs “as good as old” after self-renewal? How often can individual HSCs self-renew? Do different HSCs have different self-renewal capacities? What controls the fidelity of self-renewal? These questions remain incompletely understood. Because of their extensive self-renewal capacity, HSCs were initially thought to be immortal. This view was supported by the observation that populations of HSCs could be serially transplanted for a very long period of time- exceeding the normal lifespan of the donor[3],[4]. However, when HSCs were examined on the clonal level, extensive heterogeneity in lifespan was revealed[5]–[7]. A detailed analysis of a large panel of HSCs showed that the lifespan of individual HSCs is mathematically predictable[8]. HSCs with lifespans from 10 to nearly 60 months were found side-by-side in the same donor[8], indicating that the lifespan is pre-determined on the level of each HSC. Because lifespans of single transplanted HSCs are predictable from few initial values of their repopulation kinetic, the lifespan is a programmed HSC-specific property[8]. The population dynamics, therefore, predict that the molecular machinery which preserves self-renewal, will ultimately fail. Several hypotheses have been developed to identify and explain how HSCs limit their lifespan. The generation-age hypothesis[9] states that for every cell division, an HSC loses some quality that is referred to as “stemness”. According to Hayflick's hypothesis[10], the probability that somatic cells produce viable daughter cells which can themselves divide, decreases as the number of divisions increases. The decrease might be caused by progressive telomere shortening[10]. Hence, an extension of Hayflick's hypothesis predicts that stem cell self-renewal capacity should be self-limiting at the level of individual HSCs. Yet, HSCs and other stem cells, express telomerase[11]–[14]. This enzyme repairs telomere damage and, thus, aids in preserving genomic integrity. Thus, telomere shortening alone is unlikely to explain a limited lifespan of HSCs. Indeed, mice that have been homozygously ablated for telomerase activity show only mild effects and need to be severely stressed to reveal deficiencies in the hematopoietic system[15]. Potentially in line with these findings in mice are clinical data. It was suggested that telomerase expression declines in the long-run and may be a cause for late bone marrow transplant failure[16]. Declining telomerase expression may act in conjunction with the high stressor load imposed by the many co-morbidities affecting transplant patients[17]. Another proposal suggested that, in conjunction with oxidative stresses, high levels of reactive oxygen species( ROS) could be a damaging force acting on the long-term repopulating capacity of HSCs[18],[19]. The corresponding restoring force is provided by Forkhead box class O( FoxO) transcription factors. FoxO transcription factors increase the expression of genes whose products blunt the effects of elevated ROS[20]–[22]. That different sources of self-renewal failures could be causally co-dependent is suggested by findings that oxidative stress could shorten telomeres[23]. Along-side genome stability, the preservation of epigenetic patterning is an important prerequisite to reliably produce functional daughter HSCs upon self-renewal. It has been suggested that both maintenance and de novo methylation are needed to maintain epigenetic stability[24]. The expression levels of DNA methyltransferases[25],[26] responsible for maintenance( DNMT1) and de novo methylation( DNMT3a and DNMT3b) could be important for restoring HSC multi-potency[27],[28]. Quantitative work has suggested that small failures may accumulate over time in the DNMT1 pathways leading to the loss of maintenance methylation and, ultimately, epigenetic stability[29]. Yet, neither of these mechanisms and hypotheses explain how HSCs with different lifespans co-exist in a single host. It was suggested that HSCs could preserve their functional integrity over long periods of time by alternating between two states, called resting or quiescent, and active, respectively[30]–[32]. This idea poses that intermittent transitions to quiescence could provide the time needed to minimize the detrimental effects of repeated DNA replication and other stresses on the HSC population as a whole[33]. Elegant mathematical models of this idea have been formulated[34]–[36]. Surprisingly, quiescence may leave HSCs more vulnerable to mutations following DNA repair[37]. Quiescent and active HSCs may use different DNA repair mechanisms and the restoring pathway used by quiescent HSCs may lead to higher differentiation probabilities following re-activation. Never-the-less, when HSC quiescence was inhibited by the expression of the Wnt inhibitor Dickkopf-1, the HSC pool exhausted prematurely[38]. This suggests that periods of rest in the niche are essential for controlling HSC lifespan- supporting the idea that repair is necessary to maintain HSC lifespan. Mathematically, the lifespan of populations has been addressed in manufacturing, engineering, actuarial and biological applications of reliability theory[39]. Reliability theory was first developed as a quality control tool to predict the time-to-failure- the manufacturing term for lifespan- of manufactured goods to determine warranty times. When examined as a population, the lifespan of manufactured goods proceeds through well-defined phases( Figure 1). First, a decline in population size is found, which is interpreted as failure due to factory error. Second, there is a period of little change, known as the useful phase of the population of goods. Thereafter, the population size declines again, this time caused by age-related failure of essential machine components( wear-out phase). The second phase can be prolonged, if goods are repaired. If repairs occur repeatedly, the useful life will be extended, yet the population of goods will fail in the end, because of a general deterioration of many essential parts. In biology, failure theory has been applied to develop general laws of aging and longevity[40]–[42], respector-ligand dissociation[43], or genome instability[44]. Here, we show that the principles of reliability and failure can be exploited to craft a new model of HSC self-renewal suggesting that HSCs differ a priori in the number of( self-) repair cycles they can undergo.
Discussion:
Clonal hematopoiesis begins with a single HSC and ends with its loss after months to years[4]–[8]. During this period of time- the lifespan-, the genetic/epigenetic program of the original HSC is replicated to many daughter HSCs. In HSC self-renewal, discrepancies between replicates should be vanishingly small. Yet, clones extinguish after a limited time, suggesting that self-renewal may not be perfectly reliable in the long-run. Working from repopulation kinetics, we needed to develop quantitative measures of reliability, failure and repair that capture events of magnitudes that approach population size. Our data show that increases in failure rates associate with increasing population-wide failure loads, and decreases relate to dissipative effects of the collective repair strength. Together, the fluctuation patterns of the failure rate kinetics characterize the summary dynamics of microscopic failure and repair events at the macroscopic level of clonal HSC populations. Our approach does not depend on particular failure sources and repair mechanisms. An advantage, therefore, is that our current understanding of stem cell Omics is not limiting. Rather, reliability theory could open new avenues for interpreting longitudinal network data. For example, we make the prediction that repair capability stays approximately constant through the lifespan of an individual HSC. Constancy does not mean that individual repair mechanisms are unaffected by failure inducing processes. Instead, the function of a deteriorating repair mechanism could be taken over by an alternative pathway. We predict that the repopulation failure rate kinetics stay at low levels for a long time, but will never revert to zero failure rate. This supports the conclusion that failures are continuously generated, but are never completely cleared. Indeed, failure rates increase slowly, indicating that failures accumulate. Evidence of failure accumulation is not only seen in our experimental data. It also followed by mathematical proof( M&M section; Theorem 2) for the deterministic failure rate kinetics derived from our previously developed ballistic model[8]. Daughter HSCs of successive generations may, thus, carry an increasing failure load- consistent with previous experimental findings on the aging of HSCs[60]. As shown here, increasing failure load coupled with constant repair capacity is key to explaining the differences in lifespans of HSCs in a single host in the absence of strong extrinsic perturbations( e. g., expression of the Wnt inhibitor Dickkopf 1[38]). These predictions could be tested experimentally using longitudinal genome studies comparing genetic networks in myeloid-biased( My-bi) and lymphoid-biased( Ly-bi) HSCs[47]. The former are typically longer lived than the latter. Reliability analysis may aid in predicting universal check-points( such as in Theorem 2) to meaningfully time longitudinal genome studies of My-bi and Ly-bi HSCs. So far, the genome of My-bi HSCs has only been mined at isolated instances[47],[61]. Timing of genomic analyses is experimentally challenging, since HSCs are rare relative to mature blood cell populations. We showed that the failure rate is stable, but “noisy”. This “noise”, properly classified using rescaled range, or Hurst, analysis[53] shows how stability is generated. The experimental failure rate kinetics alternate irregularly around the deterministic failure rate component, which we used as the mean value in our rescaled range analysis of the data. We found that the Hurst exponent is for the failure rate kinetics of all long-term repopulating HSCs. HSCs with lifespans greater than one mouse life have smaller exponents than for lifespans below one mouse life. Using non-linear time series theory, we could conclude that an anti-persistent, or mean-reverting, regime governs the time period where failure rates are at a minimum. The implication is that the interaction between failure-generating mechanisms, such as HSC self-renewal divisions, and failure-dissipating processes, or repairs, creates a self-organized failure-repair equilibrium. An HSC clone exits the equilibrium state, and becomes extinct shortly there-after, when failure load has accumulated sufficiently to surpass repair capacity. Our reliability analysis of HSCs has implications on aging in HSCs[2],[45],[62] and in other non-homogenous, hierarchically organized, cell systems. The elegant general theory of aging developed by the Gavrilovs[40]–[42]- tested extensively for populations of organisms but less for those of cells[43],[44]- poses that aging systems have three properties: redundancy, initial damage load, and redundancy depletion. For HSCs, redundancy emerges over time as a function of self-renewals. The declining quality of genome replicates, due to imperfect repair as predicted here, quantifies the rate of redundancy depletion in HSCs. The mathematical results of this paper predict that the failure dissipation rate determined from our data provides a quantitative measure of “progressive damage load” starting from an HSC-specific “initial damage load”. However, what constitutes “initial damage load” in the biology of HSCs, and what its sources are, must first be investigated experimentally- primarily to address the question of how HSCs are programmed during early development.
All hematopoietic stem cells ( HSCs ) are characterized by the capacities to produce all blood cell-types by differentiation and to maintain their own population through self-renewal divisions . Every individual HSC , therefore , can generate a complete blood system , or clone , conveying oxygenation and immune protection for a limited time . The time for which all mature blood cell-types can be found in a clone is called the lifespan . Interestingly , HSCs with different lifespans co-exist in the same host . We address the unresolved question: what controls the lifespan of HSCs of the same genotype exposed to the same environment ? Here , we use a new approach to multi-scale modeling based on reliability theory and non-linear dynamics to address this question . Large-scale fluctuations in the experimental failure rate kinetics of HSC clones are identified to predict small-scale , genome level , events of deep penetrance , or magnitudes that approach population size . We broadly find that one condition explains our experimental data: repair mechanisms are a priori imperfect and do not improve , nor deteriorate , during the lifespan . As a result , progressively “worse-than-old” genome replicates are generated in self-renewal . A likely interpretation of our findings is that the lifespan of adult HSCs is determined by epigenetically pre-programmed differences in repair capacity .