Bmi1 induction protects hematopoietic stem cells against pronounced long-term hematopoietic stress.

The Polycomb complex protein Bmi1 is regarded as a master regulator of hematopoietic stem cells (HSCs). In the blood system, HSCs express Bmi1 most abundantly, and Bmi1 expression wanes as cells differentiate. Furthermore, Bmi1 has been found to be overexpressed in several hematologic cancers.

Hepatic Leukemia Factor Maintains Quiescence of Hematopoietic Stem Cells and Protects the Stem Cell Pool during Regeneration.

The transcription factor hepatic leukemia factor (HLF) is strongly expressed in hematopoietic stem cells (HSCs) and is thought to influence both HSC self-renewal and leukemogenesis. However, the physiological role of HLF in hematopoiesis and HSC function is unclear. Here, we report that mice lacking Hlf are viable with essentially normal hematopoietic parameters, including an intact HSC pool during steady-state hematopoiesis.

Critical Modulation of Hematopoietic Lineage Fate by Hepatic Leukemia Factor.

A gradual restriction in lineage potential of multipotent stem/progenitor cells is a hallmark of adult hematopoiesis, but the underlying molecular events governing these processes remain incompletely understood. Here, we identified robust expression of the leukemia-associated transcription factor hepatic leukemia factor (Hlf) in normal multipotent hematopoietic progenitors, which was rapidly downregulated upon differentiation. Interference with its normal downregulation revealed Hlf as a strong negative regulator of lymphoid development, while remaining compatible with myeloid fates.

The slippery slope of hematopoietic stem cell aging.

The late stages of life, in most species including humans, are associated with a decline in the overall maintenance and health of the organism. This applies also to the hematopoietic system, where aging is not only associated with an increased predisposition for hematological malignancies, but also identified as a strong comorbidity factor for other diseases. Research during the last two decades has proposed that alterations at the level of hematopoietic stem cells (HSCs) might be a root cause for the hematological changes observed with age.

Clonal reversal of ageing-associated stem cell lineage bias via a pluripotent intermediate.

Ageing associates with significant alterations in somatic/adult stem cells and therapies to counteract these might have profound benefits for health. In the blood, haematopoietic stem cell (HSC) ageing is linked to several functional shortcomings. However, besides the recent realization that individual HSCs might be preset differentially already from young age, HSCs might also age asynchronously.

Concise review: hematopoietic stem cell aging and the prospects for rejuvenation.

Because of the continuous increases in lifetime expectancy, the incidence of age-related diseases will, unless counteracted, represent an increasing problem at both the individual and socioeconomic levels. Studies on the processes of blood cell formation have revealed several shortcomings as a consequence of chronological age. They include a reduced ability to mount adaptive immune responses and a blood cell composition skewed toward myeloid cells, with the latter coinciding with a dramatically increased incidence of myelogenous diseases, including cancer.

Hematopoietic stem cells are intrinsically protected against MLL-ENL-mediated transformation.

Studies of developmental pathways of hematopoietic stem cells (HSCs) have defined lineage relationships throughout the blood system. This is relevant to acute myeloid leukemia (AML), where aggressiveness and therapeutic responsiveness can be influenced by the initial stage of transformation. To address this, we generated a mouse model in which the mixed-lineage leukemia/eleven-nineteen-leukemia (MLL-ENL) transcription factor can be conditionally activated in any cell type.

Induced hematopoietic stem cells: unlocking restrictions in lineage potential and self-renewal.

Obtaining sufficient numbers of immunologically matched hematopoietic stem cells (HSCs) poses a major clinical hurdle in bone marrow transplantation therapies. In a recent study in Cell, Riddell et al. (2014) generate induced HSCs from differentiated blood cells, which may serve as a potential solution to this clinical challenge.

Somatic cells with a heavy mitochondrial DNA mutational load render induced pluripotent stem cells with distinct differentiation defects.

It has become increasingly clear that several age-associated pathologies associate with mutations in the mitochondrial genome. Experimental modeling of such events has revealed that acquisition of mitochondrial DNA (mtDNA) damage can impair respiratory function and, as a consequence, can lead to widespread decline in cellular function. This includes premature aging syndromes.

An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state.

Aging of hematopoietic stem cells (HSCs) leads to several functional changes, including alterations affecting self-renewal and differentiation. Although it is well established that many of the age-induced changes are intrinsic to HSCs, less is known regarding the stability of this state. Here, we entertained the hypothesis that HSC aging is driven by the acquisition of permanent genetic mutations.

Reduced repression of cytokine signaling ameliorates age-induced decline in hematopoietic stem cell function.

Aging causes profound effects on the hematopoietic stem cell (HSC) pool, including an altered output of mature progeny and enhanced self-propagation of repopulating-defective HSCs. An important outstanding question is whether HSCs can be protected from aging. The signal adaptor protein LNK negatively regulates hematopoiesis at several cellular stages.

Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes distinct from physiological stem cell aging.

Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understanding the aging process.