Bone Marrow Tissue Organization
The bone marrow is a highly complex tissue composed of multiple hematopoietic and non-hematopoietic components including osteolineage, mesenchymal stroma and endothelial cells, neuronal structures as well as extracellular matrix proteins. We have previously quantified the spatial distribution and protein co-expression of >40 key bone marrow populations at the single-cell protein level and tissue-wide scale in situ (Nature Biotechnology, 2017). In addition, we contributed in further studies dissecting the heterogeneity of the bone marrow microenvironment in homeostasis, stress and cancer at the transcriptome and protein level, by single-cell RNA sequencing (Cell, 2019) and mass cytometry (Cell Stem Cell, 2019), respectively.
Cover from our Nature Biotechnology paper, 2017 (Image credit: Kokkaliaris, Coutu, Kunz) &
our Blood paper 2020 (Image credit: Kokkaliaris & Schroeder)
Hematopoietic Stem Cell Niche
Hematopoietic stem cells (HSCs) reside in defined anatomical microenvironments, termed niches. Despite extensive research, the cellular composition of the bone marrow HSC niche is controversial. We systematically quantified the exact localization of functionally distinct HSC subsets in relation to up to 4 simultaneously (9 in total) putative BM niches in >150 bone samples from 3 different mouse reporter systems [α-catulin-GFP (Acar et al., 2015); MFG (Christodoulou, ..., Kokkaliaris, ... et al., 2020); SCL-tTA:H2B-GFP (Wilson et al., 2008)]. We showed that adult HSCs reside in complex environments composed of sinusoids, Cxcl12-stroma and often megakaryocytes, but in frequencies reflecting the abundance of those BM populations (Blood, 2020).
Video from our Blood paper, 2020 (Video credit: Kokkaliaris)
The Bone Marrow Microenvironment in Cancer
Cancer-initiating cells are not just individual entities, but part of a complex cellular and molecular ecosystem, termed tumor microenvironment. It is currently known that malignant cells reciprocally interact with their bone marrow microenvironment(s) to drive disease progression, often at the expense of healthy hematopoiesis. Our lab is interested in defining those functional interactions and design intervention strategies to support healthy tissue function.
Figure from our Blood Advances review, 2020
Quantitative Multiplex Tissue Imaging
Due to its biophysical properties and complexity, the bone marrow has been one of the most challenging tissues to profile. Reliable identification of rare cells within their complex bone marrow microenvironments requires volumetric tissue-wide imaging with sub-cellular resolution, simultaneous detection of multiple colors/markers on samples with preserved tissue architecture and robust/efficient image analysis pipeline. Our quantitative multiplex tissue imaging approach fulfills those requirements and can be extended to any tissue (Nature Methods, 2018). Our lab aims at further developing tissue imaging modalities to capture the uncovered complexity of the bone marrow microenvironment.