Hematopoietic stem cell (HSC) function undergoes significant changes during development and upon aging. Aged HSCs have low and myeloid-biased regenerative potential compared to young HSCs. This myeloid- biased differentiation of HSCs is postulated to be at least partially responsible for the impaired adaptive immune system observed in elder population, a significant health concern for elders increasing the incidence of infectious diseases. The prevailing view is that HSC aging is regulated by both HSC intrinsic and extrinsic changes. A significant barrier in understanding how HSC aging is affected by cell extrinsic changes is the fact that aging affects multiple organs, and that HSCs are regulated by multiple organs and cell types within the HSC supportive microenvironment (HSC niche) in the bone marrow. Here, we propose to dissect the complex biology of aging by introducing age-related changes to one cell type within the HSC niche, the mesenchymal stromal cells (MSCs), and determine whether changes in MSCs cause age-related changes in HSCs and hematopoiesis. We have found that an anti-senescence factor Bmi1 is highly expressed in MSCs compared to other cells in the bone marrow, and that Bmi1 expression levels in MSCs decline with age. We then discovered that conditionally deleting Bmi1 from MSCs causes senescence and expands adipocytes in the bone marrow, similar to what happens in human aging. These age-related changes in MSC function caused age-related changes in HSC and hematopoiesis, including anemia, loss of bone marrow cellularity, and strikingly, myeloid- biased differentiation of HSCs. All of these changes in HSCs and hematopoiesis are hallmarks of aging in HSCs and hematopoiesis. We thus hypothesized that age-related changes induced in MSCs by deleting Bmi1 causes age-related changes in HSCs. Our long term goal is to understand how HSC aging is regulated cell extrinsically by the HSC niche. Our new model provides a unique opportunity to focus on changes in HSC function caused specifically by changes in bone marrow MSCs. We have two broad aims to study how Bmi1 in MSCs regulate HSCs and hematopoiesis.
In aim 1, we will determine whether the HSC and hematopoiesis phenotypes after deleting Bmi1 from MSCs become exacerbated with advanced age or by inflammation. We will also examine whether HSC engraftment and mobilization are also affected by deleting Bmi1 from MSCs.
In aim 2, we will determine whether induction of senescence or adipogenesis upon Bmi1 deletion from MSCs impairs the HSC niche function, by conditionally deleting senescence regulators Ink4a/Arf, or adipogenesis regulators PPAR? and Prdm16. We will also examine the molecular mechanism by which Bmi1 regulates PPAR? and Prdm16. Upon completion of this work, we will have a deep understanding of how changes in HSC niche induced by altered MSC function causes age-related changes in HSCs. This may lead to novel intervention to increase HSC function via MSC in vitro and in vivo, and better conditioning regimens for elder bone marrow transplant recipients to increase HSC engraftment and function by improving MSC function.
Aging impairs hematopoietic stem cell function by reducing the regenerative potential and skewing their differentiation towards myeloid cells at the expense of producing lymphoid cells. We have found that aging of hematopoietic stem cells is affected by the age-related changes that occur in mesenchymal stromal cells, precursors of osteoblasts and adipocytes in the bone marrow. Understanding how mesenchymal stromal cells regulate hematopoietic stem cell aging may lead to novel intervention to alleviate hematopoietic stem cell aging, thereby improving the function of the immune system of the elder population.
|Gundry, Michael C; Brunetti, Lorenzo; Lin, Angelique et al. (2016) Highly Efficient Genome Editing of Murine and Human Hematopoietic Progenitor Cells by CRISPR/Cas9. Cell Rep 17:1453-1461|