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Laboratory for Growth Factors and Stem Cells
Our laboratory's main objective is to comprehend the molecular mechanisms governing tissue homeostasis. Through this understanding, we aim to develop innovative regenerative therapies. Our focus lies on studying the mammalian bone marrow microenvironment (also known as the niche). This niche plays a crucial role in maintaining two separate lineages of stem cells: hematopoietic stem cells (HSC) responsible for blood production, and skeletal stem cells (SSC) involved in bone and fat formation. Our primary interest is in investigating the various secreted factors that regulate these stem cells, including growth factors, extracellular matrix proteins, and more.
Growth Factors for Stem Cells
The regulation of adult stem cells in specialized tissue microenvironments (niches) relies on the secretion of key growth factors by niche cells. These growth factors are essential for maintaining the self-renewal and differentiation of adult stem cells. Understanding the regulatory mechanisms of these growth factors within the niche not only provides insights into the regulation of stem cells but also holds significant potential for advancements in regenerative medicine. In our laboratory, we have a primary focus on identifying and characterizing the activities of growth factors in the bone marrow, which are crucial for regulating hematopoietic stem/progenitor cells as well as skeletal stem/progenitor cells. We utilize a systematic genetic approach to identify previously undiscovered stem cell growth factors, focusing on extracellular matrix proteins (ECM proteins) or matrisome proteins. Our team is particularly interested in the factor Osteolectin/Clec11a, which has been found to promote the osteogenic differentiation of bone marrow stromal cells through integrin alpha11 and Wnt activation (eLife 5:e18782; eLife 8:e42274). By unraveling the functions of such growth factors and identifying their potential receptors, we aim to unveil new and actionable targets for the treatment of various conditions, including osteoporosis and other diseases.
Integrin alpha11, a receptor for Osteolectin, are required for the maintenance of adult skeleton. Image from Shen et al., eLife, 2019
A mechanosensitive peri-arteriolar niche for lymphoid progenitors and osteogenic proteniors, Image from Saçma and Geiger, Nature News & Views, 2021
Heterogeneity of Stem Cell Niches
Adult bone marrow LepR+ cells are heterogeneous, containing sub-populations including skeletal stem cells, osteogenic progenitors, adipogenic progenitors, fibroblasts, etc (Dev Cell 54:639). One such sub-population we identified was the Osteolectin-expressing peri-arteriolar osteogenic progenitors, which are mechanosensitive and required for both osteogenesis and maintenance of lymphoid progenitors (Nature 591:438). Using a combination of mouse genetics and novel antibodies, we are characterizing other sub-populations of LepR+ cells. We believe that the identification of these cell populations would further our understanding about the bone marrow niches for hematopoiesis and osteogenesis, with the potential to provide new insights in targeting blood and bone diseases.
Neural Regulation of Stem Cells
We are currently focused on exploring the fascinating field of neural regulation in stem cell biology. Specifically, our research aims to investigate the role of peripheral nerves in regulating tissue homeostasis and promoting regeneration. In our recent findings, we made an exciting discovery that bone marrow innervation is primarily maintained by NGF (Nerve Growth Factor) synthesized by LepR+ cells. These specific cells, marked by the presence of leptin receptors, play a crucial role in promoting bone marrow innervation and regeneration through the synthesis of nerve growth factor. Through our investigations, we observed that after myeloablation, LepR+ cells and their derived adipocytes increased production of NGF, thereby stimulating nerve sprouting within the bone marrow and facilitating hematopoietic and vascular regeneration. This process was facilitated by the activation of β2 and β3 adrenergic receptor signaling in LepR+ cells, as well as potentially in adipocytes, leading to the increased production of various growth factors essential for hematopoietic and vascular regeneration. This regeneration process is facilitated by the activation of β2 and β3 adrenergic receptor signaling in both LepR+ cells and adipocytes, resulting in an increase in the production of various growth factors necessary for hematopoietic and vascular regeneration. This reciprocal relationship between peripheral nerves and LepR+ cells plays a crucial role in promoting bone marrow regeneration, as LepR+ cells sustain nerves by synthesizing NGF while the nerves, in turn, enhance regeneration by promoting the production of growth factors by LepR+ cells (Nat Cell Biol 25:1746). Our ongoing research focuses on gaining a deeper understanding of the mechanisms that underlie the regulation of regeneration by nerves in bone marrow, as well as in other organs.
Leptin receptor+ cells promote bone marrow innervation and regeneration by synthesizing nerve growth factor. Image from Gao et al., Nat Cell Biol, 2023
Mechanic Regulation of Stem Cells
Our research focuses on exploring novel mechanisms that regulate stem cells, particularly in understanding how mechanical forces impact tissue homeostasis at a molecular level. A key aspect of this investigation involves studying the effects of mechanical force on osteogenic progenitors and their maintenance, as demonstrated in our previous work (Nature 591:438). Over the years, various mechanosensing receptor families have been identified as crucial in governing cellular responses to mechanical forces, promoting tissue homeostasis and facilitating injury repair. Through a combination of cellular and molecular approaches, we aim to uncover the specific molecular mechanisms that these cells employ to detect and respond to mechanical force. Of particular interest to our studies are adherent cells, specifically LepR+Oln+ cells (Nature 591:438), as well as non-adherent cells like platelets (Nature 503:131). By comparing and contrasting the mechanosensing mechanisms and signaling pathways utilized by these different cell types, we hope to gain valuable insights into their similarities and differences.
Arterioles and arteries are much more efficient in propagating mechanical force than sinusoids due to their stiffness in computational modeling. Image from Zhao et al., Advanced Healthcare Materials, 2023