Hematopoietic stem cells (HSCs) reside in specialized microenvironments (niches) in the bone marrow. There is emerging evidence that distinct populations of mesenchymal stromal cells in the bone marrow regulate specific subsets of hematopoietic stem/progenitor cells (HSPC), including HSCs themselves. The transforming growth factor (TGF) superfamily includes TGF-?s, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), and activins. The contribution of TGF family member signaling to the establishment and maintenance of hematopoietic niches is largely unknown. Our preliminary data show that loss of TGF-? signaling in BM stromal cells results in the disruption of the B-lymphoid niche but preserves the stem cell niche. In contrast, prior studies suggest that BMP or activin/GDF signaling in BM stromal cells contributes to the maintenance of the stem cell and erythroid niches, respectively. These observations suggest the hypothesis that different TGF family members may regulate distinct types of hematopoietic niches. There is evidence that expression of TGF family members in the bone marrow is regulated by environmental signals. Indeed, our preliminary data show that TGF-? signaling is activated in stromal cells following treatment with G-CSF. These data suggest the hypothesis that TGF family signaling in mesenchymal stromal cells is an important mechanism to modify hematopoietic niches in response to environmental stresses. Since drugs that modulate the activity of several TGF family members are in development, this research may suggest novel approaches to modulate hematopoietic niches for therapeutic benefit.
Aim 1. To characterize the contribution of TGF family member signaling in the maintenance and function of mesenchymal stromal cells implicated in hematopoietic niches. We will generate mice carrying deletions of the three type II TGF receptors expressed in mesenchymal stromal cells: Tgfbr2, which mediates TFG-? signaling; Acvr2a, which mediates activin, GDF, and BMP signaling; and Bmpr2, which mediates BMP signaling. We also will postnatally delete Smad4, which is required for all canonical TGF family member signaling. In each case, we will quantify and assess the function of stromal cells implicated in hematopoietic niche maintenance, including mesenchymal stem cells, pericytes, CXCL12-abundant reticular (CAR) cells, and mature osteoblasts in the bone marrow of adult mice.
Aim 2. To characterize the role of TGF family member signaling in mesenchymal stromal cells in the regulation of hematopoiesis. Here, we will characterize basal and stress hematopoiesis in the transgenic mice carrying targeted deletions of TGF receptors described in Aim 1. In particular, we will assess the contribution of TGF family member signaling in G-CSF induced HSPC mobilization and suppression of B lymphopoiesis, the stress erythropoiesis response, and hematopoietic recovery from myeloablative chemotherapy.
Proper functioning of hematopoietic stem/progenitor cells (HSPCs) is essential to maintain normal blood counts. HSPC function is dependent on signals from stromal cells in the bone marrow. This research is focused on understating how members of the transforming growth factor (TGF) superfamily regulate bone marrow stromal cells. This research may lead to novel strategies to use drugs that target TGF family members to treat blood disorders.
| Yao, Juo-Chin; Link, Daniel C (2017) Concise Review: The Malignant Hematopoietic Stem Cell Niche. Stem Cells 35:3-8 |
| Zhang, Jingzhu; Link, Daniel C (2016) Targeting of Mesenchymal Stromal Cells by Cre-Recombinase Transgenes Commonly Used to Target Osteoblast Lineage Cells. J Bone Miner Res 31:2001-2007 |
