Global transcriptomic profiling of the bone marrow stromal microenvironment during postnatal development, aging and inflammation

Abstract

Bone marrow (BM) stromal cells provide the structural and regulatory framework for hematopoiesis and contribute to developmental-stage specific niches, such as those preserving hematopoietic stem cell (HSCs). Despite recent advances in our understanding of stromal composition and function, little is known on the dynamic transcriptional remodeling that this compartment undergoes over time and during adaptation to stress. Similarly, how molecular changes in stroma are linked to age-related modulation of hematopoiesis is poorly understood. Using RNA-sequencing, we performed a longitudinal comparison of the transcriptional profile of four principal mesenchymal and endothelial stromal subsets, namely CXCL12-abundant reticular (CARc), PDGFR-α + Sca-1 + , sinusoidal (SECs) and arterial endothelial cells (AECs), isolated from early postnatal, adult and aged mice. Our data i) provide molecular fingerprints defining novel, cell-specific anatomical and functional features ii) reveal radical reprogramming of pro-hematopoietic, immune and matrisomic transcriptional programs during the narrow temporal transition from juvenile to adult stages iii) demonstrate that homeostatic aging is characterized by a progressive and pronounced upregulation of pro-inflammatory gene-expression and loss of stromal cell fitness. By profiling in vivo responses of stromal cells to infection-mimicking agents, we finally demonstrate that transcriptomic pathways elicited by sterile inflammation are largely recapitulated during aging, thereby supporting the inflammatory basis of aging-related adaptations of BM hematopoietic function. Transcriptomic profiling of BM stroma Helbling et al.

Bone marrow Tregs mediate stromal cell function and support hematopoiesis via IL-10

“…These findings highlight the differential effects between transient and prolonged IL-10 perturbations on stroma. Our observations suggest that acute perturbations of Tregs/IL-10, as seen with anti-CD25, IL-10R blockage, and FTY720, lead to increased stromal proliferation, consistent with a stress response (80). Conversely, lifelong loss of IL-10 signaling, as seen with genetic deletions, appears to hamper stromal cell maturation, resulting in decreased numbers.…”

Regulation of the Bone Marrow Niche by Inflammation

“…Niche cell populations may regulate the hematopoietic response to peripheral inflammation or infection, for instance, by releasing factors that promote myelopoiesis ( 5 , 32 , 33 ) ( Figure 2A ). Such a factor is granulocyte colony-stimulating factor (G-CSF), a central regulator of infection-induced emergency granulopoiesis, as it exerts a key role in the differentiation of progenitors of the myeloid lineage to mature granulocytes ( 5 ).…”

“…Another study demonstrated that treatment of mice with IFN-α or polyinosinic:polycytidylic acid (polyI:C) activates BM endothelial cells and increases vascularity and vessel permeability ( 49 ). Moreover, single-cell transcriptomic analysis revealed that the administration of polyI:C and LPS induces gene expression of the chemokines Ccl5, Ccl6, Ccl19, Cxcl9, Cxcl10 , and Cxcl11 in CXCL12-abundant reticular cells and sinusoidal endothelial cells ( 32 ). Additionally, inflammation induced the expression of Il6 and downregulated the expression of factors that contribute to HSC retention and lymphopoiesis, including Cxcl12, Kitl , and Il7 ( 32 ).…”

Clonal Hematopoiesis of Indeterminate Potential as a Novel Risk Factor for Donor-Derived Leukemia

“…Together with metabolic and epigenetic shifts, the composition of supporting cells and the levels of secreted factors in the BM microenvironment change with age ( Mendelson and Frenette, 2014 ; Verovskaya et al., 2019 ). Detected both systemically and in the BM stroma, inflammation is an important event during aging and can alter hematopoiesis ( Kovtonyuk et al., 2016 ; Helbling et al., 2019 ). As inflammation can contribute to cancer pathogenesis, one possible explanation for the development of DDL from CHIP donors is that hematopoietic lineages exhibiting pro-inflammatory phenotypes may modify the BM microenvironment and hematopoiesis to promote leukemogenesis ( Figure 2 ) ( Henry et al., 2015 ; Leimkuhler and Schneider, 2019 ).…”