Česká Genetická Banka

NATURE: 21. 11. 2013

NATURE: A canonical to non-canonical Wnt signalling switch in haematopoietic stem-cell ageing

Many organs with a high cell turnover (for example, skin, intestine and blood) are composed of short-lived cells that require continuous replenishment by somatic stem cells. Ageing results in the inability of these tissues to maintain homeostasis and it is believed that somatic stem-cell ageing is one underlying cause of tissue attrition with age or age-related diseases. Ageing of haematopoietic stem cells (HSCs) is associated with impaired haematopoiesis in the elderly^{3, 4, 5, 6}. Despite a large amount of data describing the decline of HSC function on ageing, the molecular mechanisms of this process remain largely unknown, which precludes rational approaches to attenuate stem-cell ageing. Here we report an unexpected shift from canonical to non-canonical Wnt signalling in mice due to elevated expression of Wnt5a in aged HSCs, which causes stem-cell ageing. Wnt5a treatment of young HSCs induces ageing-associated stem-cell apolarity, reduction of regenerative capacity and an ageing-like myeloid–lymphoid differentiation skewing via activation of the small Rho GTPase Cdc42. Conversely, Wnt5a haploinsufficiency attenuates HSC ageing, whereas stem-cell-intrinsic reduction of Wnt5a expression results in functionally rejuvenated aged HSCs. Our data demonstrate a critical role for stem-cell-intrinsic non-canonical Wnt5a signalling in HSC ageing."

http://www.nature.com/nature/journal/v503/n7476/full/nature12631.html

BLOOD: Amino acid substitution at peptide-binding pockets of HLA class I molecules increases risk of severe acute GVHD and mortality

"HLA disparity has a negative impact on the outcomes of hematopoietic cell transplantation (HCT). We studied the independent impact of amino acid substitution (AAS) at peptide-binding positions 9, 99, 116, and 156, and killer immunoglobulin-like receptor binding position 77 of HLA-A, B, or C, on the risks for grade 3-4 acute graft-versus-host disease (GVHD), chronic GVHD, treatment-related mortality (TRM), relapse, and overall survival. In multivariate analysis, a mismatch at HLA-C position 116 was associated with increased risk for severe acute GVHD (hazard ratio [HR] = 1.45, 95% confidence interval [CI] = 1.15-1.82, P = .0016). Mismatch at HLA-C position 99 was associated with increased transplant-related mortality (HR = 1.37, 95% CI = 1.1-1.69, P = .0038). Mismatch at HLA-B position 9 was associated with increased chronic GVHD (HR = 2.28, 95% CI = 1.36-3.82, P = .0018). No AAS were significantly associated with outcome at HLA-A. Specific AAS pair combinations with a frequency >30 were tested for association with HCT outcomes. Cysteine to tyrosine substitution at position 99 of HLA-C was associated with increased TRM (HR = 1.78, 95% = CI 1.27-2.51, P = .0009). These results demonstrate that donor-recipient mismatch for certain peptide-binding residues of the HLA class I molecule is associated with increased risk for acute and chronic GVHD and death."

http://bloodjournal.hematologylibrary.org/content/122/22/3651.abstract