Biology subjects

Alonso-Calleja, A.

Publications and source records attributed to Alonso-Calleja, A..

3 recordsLinked to original sources

bioRxiv2024

Loss of H3K9 trimethylation leads to premature aging

Aging is the major risk factor for most human diseases and represents a major socio-economical challenge for modern societies. Despite its importance, the process of aging remains poorly understood. Epigenetic dysregulation has been proposed as a key driver of the aging process. Modifications in transcriptional networks and chromatin structure might be central to age-related functional decline. A prevalent feature described during aging is the overall reduction in heterochromatin, specifically marked by the loss of repressive histone modification, Histone 3 lysine 9 trimethylation (H3K9me3). However, the role of H3K9me3 in aging, especially in mammals, remains unclear. Here we show using a novel mouse strain, (TKOc), carrying a triple knockout of three methyltransferases responsible for H3K9me3 deposition, that the inducible loss of H3K9me3 in adulthood results in premature aging. TKOc mice exhibit reduced lifespan, lower body weight, increased frailty index, multi-organ degeneration, transcriptional changes with significant upregulation of transposable elements, and accelerated epigenetic age. Our data strongly supports the concept that the loss of epigenetic information directly drives the aging process. These findings reveal the importance of epigenetic regulation in aging and suggest that interventions targeting epigenetic modifications could potentially slow down or reverse age-related decline. Understanding the molecular mechanisms underlying the process of aging will be crucial for developing novel therapeutic strategies that can delay the onset of age-associated diseases and preserve human health at old age specially in rapidly aging societies.

physiology↗

bioRxiv2023

The bile acid receptor TGR5 regulates the hematopoietic support capacity of the bone marrow niche

The gut is an emerging regulator of bone marrow (BM) hematopoiesis, with several signaling molecules involved in this communication. Among them, bile acids (BAs) act as a relay between the microbiota and the rest of the body through the activation of specific receptors, including Takeda G protein-coupled receptor 5 (TGR5). TGR5 has potent regulatory effects in immune cells, but its role in the BM as a primary immune organ remains unknown. Here, we demonstrate that TGR5 is expressed in hematopoietic progenitors and BM stromal progenitors. TGR5 deficiency did not affect steady-state hematopoiesis but led to impaired short-term progenitor reconstitution and reduced regulated bone marrow adipose tissue (BMAT) in young male mice, but not in female mice. The reduction in BMAT was accompanied by an enrichment in BM adipocyte progenitors and was associated with enhanced hematopoietic recovery upon BM transplantation into Tgr5-/- recipients. Moreover, its reduction was associated with lower myeloid-to-lymphoid progenitor ratios in obese and in aged Tgr5-/- male mice, resembling more those of lean or young controls. Our results indicate that TGR5 is essential for maintaining a balanced BM microenvironment in a sex-dependent manner and open the possibility of modulating stromal hematopoietic support by acting on TGR5 signaling. Impact statementTGR5 loss-of-function reduced regulated bone marrow adipose tissue in male mice, without affecting that of females at homeostasis, and accelerated myeloid recovery upon bone marrow transplantation. These data highlight TGR5 as a new player in the bone marrow microenvironment.

cell biology↗

bioRxiv2023

Adrenal extramedullary hematopoiesis as an inducible model of the adult hematopoietic niche

Hematopoietic Stem and Progenitor Cells (HSPCs) reside in the hematopoietic niche, a structure that regulates the balance of cellular quiescence, self-renewal and commitment in a demand-adapted manner. The bone marrow (BM) hematopoietic niche is formed by several cellular players, mainly endothelial cells, osteoblasts, adipocytes, and stromal cells. While the BM niche forms a complex structure, evidence exists for simpler, albeit functional, extramedullary hematopoietic niches. However, the composition of what constitutes the simplest unit of an HSPC supportive microenvironment remains largely unknown. Here, we show that the adult adrenal gland can be transformed into a hematopoietic supportive environment. Upon splenectomy and hormonal stimulation, the adult adrenal gland can be induced to recruit and host HSPC function, including serial transplantation. Furthermore, the adrenal stroma contains a CXCL12+ population, reminiscent of BM CXCL12-Abundant Reticular (CAR) cells. Mirroring this, we found CXCL12+ cells in patient samples obtained from a local cohort of myelolipoma, a benign adrenal tumor composed of adipose and hematopoietic tissue that constitutes the most common site of extramedullary hematopoiesis specific to the adult. We present our model as a novel tool to increase our understanding of the physiology of hematopoietic support and to facilitate the development of a boneless niche model.

cell biology↗