Haematopoietic stem cell numbers are not solely determined by niche availability.

Haematopoietic stem cells (HSCs) reside in specialized microenvironments, also referred to as niches, and it has been widely believed that HSC numbers are determined by the niche size alone . However, the vast excess of the number of niche cells over that of HSCs raises questions about this model. We initially established a mathematical model of niche availability and occupancy, which predicted that HSC numbers are restricted at both systemic and local levels.

VCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells.

Haematopoietic stem cells (HSCs) home to the bone marrow via, in part, interactions with vascular cell adhesion molecule-1 (VCAM1). Once in the bone marrow, HSCs are vetted by perivascular phagocytes to ensure their self-integrity. Here we show that VCAM1 is also expressed on healthy HSCs and upregulated on leukaemic stem cells (LSCs), where it serves as a quality-control checkpoint for entry into bone marrow by providing 'don't-eat-me' stamping in the context of major histocompatibility complex class-I (MHC-I) presentation.

The microbiota regulates hematopoietic stem cell fate decisions by controlling iron availability in bone marrow.

Host microbiota crosstalk is essential for the production and functional modulation of blood-cell lineages. Whether, and if so how, the microbiota influences hematopoietic stem cells (HSCs) is unclear. Here, we show that the microbiota regulates HSC self-renewal and differentiation under stress conditions by modulating local iron availability in the bone marrow (BM).

Engineering a haematopoietic stem cell niche by revitalizing mesenchymal stromal cells.

Haematopoietic stem cells (HSCs) are maintained by bone marrow niches in vivo, but the ability of niche cells to maintain HSCs ex vivo is markedly diminished. Expression of niche factors by Nestin-GFP mesenchymal-derived stromal cells (MSCs) is downregulated upon culture, suggesting that transcriptional rewiring may contribute to this reduced HSC maintenance potential. Using an RNA sequencing screen, we identified five genes encoding transcription factors (Klf7, Ostf1, Xbp1, Irf3 and Irf7) that restored HSC niche function in cultured bone marrow-derived MSCs.

Induced pluripotent stem cell models of lysosomal storage disorders.

Induced pluripotent stem cells (iPSCs) have provided new opportunities to explore the cell biology and pathophysiology of human diseases, and the lysosomal storage disorder research community has been quick to adopt this technology. Patient-derived iPSC models have been generated for a number of lysosomal storage disorders, including Gaucher disease, Pompe disease, Fabry disease, metachromatic leukodystrophy, the neuronal ceroid lipofuscinoses, Niemann-Pick types A and C1, and several of the mucopolysaccharidoses. Here, we review the strategies employed for reprogramming and differentiation, as well as insights into disease etiology gleaned from the currently available models.

Efferocytosis is impaired in Gaucher macrophages.

Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylceramide-laden macrophages resulting from impaired digestion of aged erythrocytes or apoptotic leukocytes. Studies of macrophages from patients with type 1 Gaucher disease with genotypes N370S/N370S, N370S/L444P or N370S/c.84dupG revealed that Gaucher macrophages have impaired efferocytosis resulting from reduced levels of p67 and Rab7.

A New Glucocerebrosidase Chaperone Reduces α-Synuclein and Glycolipid Levels in iPSC-Derived Dopaminergic Neurons from Patients with Gaucher Disease and Parkinsonism.

Unlabelled: Among the known genetic risk factors for Parkinson disease, mutations in GBA1, the gene responsible for the lysosomal disorder Gaucher disease, are the most common. This genetic link has directed attention to the role of the lysosome in the pathogenesis of parkinsonism. To study how glucocerebrosidase impacts parkinsonism and to evaluate new therapeutics, we generated induced human pluripotent stem cells from four patients with Type 1 (non-neuronopathic) Gaucher disease, two with and two without parkinsonism, and one patient with Type 2 (acute neuronopathic) Gaucher disease, and differentiated them into macrophages and dopaminergic neurons.

Varied autopsy findings in five treated patients with Gaucher disease and parkinsonism include the absence of Gaucher cells.

Enzyme replacement therapy is standard of care for patients with Gaucher disease, as it significantly improves skeletal, visceral, and hematological symptoms. Few pathological studies have documented the extent of pathological findings in treated patients. Autopsy findings in five treated patients, who ultimately developed parkinsonism, ranged from the complete absence of Gaucher pathology to extensive involvement of multiple tissues, without correlation to age, genotype, spleen status, or dose/duration of therapy.

Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages.

Gaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylcer-amide macrophages, the accumulation of glucosylceramide in lysosomes and the secretion of inflammatory cytokines. However, the connection between this lysosomal storage and inflammation is not clear. Studying macrophages derived from peripheral monocytes from patients with type 1 Gaucher disease with genotype N370S/N370S, we confirmed an increased secretion of interleukins IL-1β and IL-6.

New macrophage models of Gaucher disease offer new tools for drug development.

Gaucher disease is an inherited enzyme deficiency resulting in the lysosomal accumulation of specific glycolipids in macrophages and, in some cases, neurons. While current treatments are effective at reducing this glycolipid storage in macrophages, they are expensive and ineffective in treating neurological manifestations of the disease, driving the search for novel therapeutics. Moreover, mutations in , the gene implicated in Gaucher disease, are an important risk factor for the development of Parkinson disease and related disorders, an association that has further heightened interest in Gaucher disease research.

Daughterless homodimer synergizes with Eyeless to induce Atonal expression and retinal neuron differentiation.

Class I Basic Helix-Loop-Helix (bHLH) transcription factors form homodimers or heterodimers with class II bHLH proteins. While bHLH heterodimers are known to have diverse roles, little is known about the role of class I homodimers. In this manuscript, we show that a linked dimer of Daughterless (Da), the only Drosophila class I bHLH protein, activates Atonal (Ato) expression and retinal neuron differentiation synergistically with the retinal determination factor Eyeless (Ey).