Projects

The stem cell niche of myelodysplastic syndrome

The lack of second-line treatment for the aged remains a major bottleneck to improve prognosis in myelodysplastic syndromes (MDS), presenting an urgent need in finding novel molecular mechanisms that govern MDS progression. The bone marrow microenvironment has been suggested as a critical player in MDS. Recent advances in imaging technologies further revealed that healthy and leukemic cells exhibit unique spatial landscapes in the bone marrow because the fate commitment of these cells relies on crosstalk with just a subset of endothelium, peri-vascular stroma, endosteal or immune cells, termed the “niche”. Using intravital imaging, we aim to identify potential therapeutic candidates by determining critical components in the niche that participate in disease propagation, especially in leukemic evolution. 

The interplay of bone remodeling and the bone marrow microenvironment for normal hematopoiesis and malignancies

Hematopoietic stem cells (HSCs) can reconstitute the blood and immune systems through tightly regulated fate decisions that balance self-renewal and multi-lineage differentiation. The stem cell niche is the bone marrow microenvironment surrounding HSCs and provide functional cues to the cells. On top of the well-recognized niche factors such as bone cells, vascular endothelium, bone marrow stroma, and their secreting factors, recent work suggested that expansion of HSCs and leukemic cells are restricted to bone marrow cavities harboring bone resorptive activities. The observation suggested that BM cavities are not the same, where distinct stages of bone remodeling may impose a heterogeneity in the known stem cell niche, but the underlying mechanisms remain largely unaddressed. As the bone is undergoing constant remodeling, and such process can be altered significantly in aging and cancer, understanding how it works in concert with the bone marrow microenvironment will provide additional handles to manipulate the fate of HSCs in emergency hematopoiesis and in age-associated blood disorders.

Intravital pH sensing of the cancer microenvironment

Acidosis has recently gained recognition as an independent microenvironment stressor that, irrespective of hypoxia, can promote survival and proliferation of cancer cells. Mild acidification has been found to correlate with appearance of several hallmarks of elevated energy metabolism favoring anabolic processes required for cancer cell division and growth. We previously developed in vivo, absolute quantification of interstitial pH at single cell resolution. The tool will enable us to study microenvironmental acidosis in the context of healthy hematopoiesis and leukemia.

Visualizing and manipulating the communicative network of bone marrow stromal cells

Bone marrow stromal cells (BMSCs) are one of the key niches for the maintenance of hematopoietic stem cells. This work in collaboration with Dr. Charles Lin at MGH is to use in vivo imaging in combination of spatially resolved molecular/functional analyses to decode how BMSCs achieve coordinative function during healthy and stressed hematopoiesis.