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The cellular composition and function of the bone marrow niche after allogeneic hematopoietic cell transplantation.

ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for patients with a variety of malignant and non-malignant diseases. Despite its life-saving potential, HCT is associated with significant morbidity and mortality. Reciprocal interactions between hematopoietic stem cells (HSCs) and their surrounding bone marrow (BM) niche regulate HSC function during homeostatic hematopoiesis as well as regeneration. However, current pre-HCT conditioning regimens, which consist of high-dose chemotherapy and/or irradiation, cause substantial short- and long-term toxicity to the BM niche. This damage may negatively affect HSC function, impair hematopoietic regeneration after HCT and predispose to HCT-related morbidity and mortality. In this review, we summarize current knowledge on the cellular composition of the human BM niche after HCT. We describe how pre-HCT conditioning affects the cell types in the niche, including endothelial cells, mesenchymal stromal cells, osteoblasts, adipocytes, and neurons. Finally, we discuss therapeutic strategies to prevent or repair conditioning-induced niche damage, which may promote hematopoietic recovery and improve HCT outcome.

SUBMITTER: Peci F

PROVIDER: S-EPMC9187885 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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The cellular composition and function of the bone marrow niche after allogeneic hematopoietic cell transplantation.

Peci Flavia F Dekker Linde L Pagliaro Anna A van Boxtel Ruben R Nierkens Stefan S Belderbos Mirjam M

Bone marrow transplantation 20220611 9

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for patients with a variety of malignant and non-malignant diseases. Despite its life-saving potential, HCT is associated with significant morbidity and mortality. Reciprocal interactions between hematopoietic stem cells (HSCs) and their surrounding bone marrow (BM) niche regulate HSC function during homeostatic hematopoiesis as well as regeneration. However, current pre-HCT conditioning regimens, which consist ...[more]

PMID: 35690693

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Project description:BackgroundAllogeneic hematopoietic stem cell transplantation (AHSCT) is a curative therapeutic approach for different hematological malignancies (HMs), and epigenetic modifications, including DNA methylation, play a role in the reconstitution of the hematopoietic system after AHSCT. This study aimed to explore global DNA methylation dynamic of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs) from donors and their respective recipients affected by acute myeloid leukemia (AML), acute lymphoid leukemia (ALL) and Hodgkin lymphoma (HL) during the first year after transplant.MethodsWe measured DNA methylation profile by Illumina HumanMethylationEPIC in BM HSPC of 10 donors (t0) and their matched recipients at different time points after AHSCT, at day + 30 (t1), + 60 (t2), + 120 (t3), + 180 (t4), and + 365 (t5). Differential methylation analysis was performed by using R software and CRAN/Bioconductor packages. Gene set enrichment analysis was carried out on promoter area of significantly differentially methylated genes by clusterProfiler package and the mSigDB genes sets.ResultsResults show significant differences in the global methylation profile between HL and acute leukemias, and between patients with mixed and complete chimerism, with a strong methylation change, with prevailing hyper-methylation, occurring 30 days after AHSCT. Functional analysis of promoter methylation changes identified genes involved in hematopoietic cell activation, differentiation, shaping, and movement. This could be a consequence of donor cell "adaptation" in recipient BM niche. Interestingly, this epigenetic remodeling was reversible, since methylation returns similar to that of donor HSPCs after 1 year. Only for a pool of genes, mainly involved in dynamic shaping and trafficking, the DNA methylation changes acquired after 30 days were maintained for up to 1 year post-transplant. Finally, preliminary data suggest that the methylation profile could be used as predictor of relapse in ALL.ConclusionsOverall, these data provide insights into the DNA methylation changes of HSPCs after transplantation and a new framework to investigate epigenetics of AHSCT and its outcomes.

Project description:Allogeneic hematopoietic stem cell transplantation (AHSCT) is a life-saving treatment for selected hematological malignancies. So far, it remains unclear whether transplanted hematopoietic stem/progenitor cells (HSPCs) undergo epigenetic changes upon engraftment in recipient bone marrow (BM) after AHSCT and whether these changes might be useful in the transplant diagnostics. The purpose of this study was to characterize the whole genome methylation profile of HSPCs following AHSCT. Moreover, the relationship between the observed methylation signature and patient outcome was analyzed. Mobilized peripheral blood (mPB)-HSPCs from seven donors and BM-HSPCs longitudinally collected from transplanted patients with hematological malignancies up to one year from AHSCT (a total of twenty-eight samples) were analyzed using DNA methylation based-arrays. The obtained data showed that DNA methylation of mPB-HSPCs differs between young and adult donors and changes following HSPC engraftment in the BM of recipient patients. Looking at methylation in promoter regions, at 30 days post-AHSCT, BM-HSPCs showed a higher number of differentially methylated genes (DMGs) compared to those of mPB-HSPCs, with a prevalent hyper-methylation. These changes were maintained during all the analyzed time points, and methylation became like the donors after one year from transplant. Functional analysis of these DMGs showed an enrichment in cell adhesion, differentiation and cytokine (interleukin-2, -5 and -7) production and signaling pathways. Of note, DNA methylation analysis allowed to identify a potential "cancer/graft methylation signature" of transplant failure. It was evident in the latest available post-transplant BM-HSPC sample (at 160 days) and surprisingly already in early phase (at 30 days) in patients whose transplant was doomed to fail. Overall, the analysis of HSPC methylation profile could offer useful prognostic information to potentially assess engraftment success and predict graft failure in AHSCT.

Dataset Information

The cellular composition and function of the bone marrow niche after allogeneic hematopoietic cell transplantation.

Publications

The cellular composition and function of the bone marrow niche after allogeneic hematopoietic cell transplantation.

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