Ambrosi Lab | Orthopaedics | UC Davis Health

Tom’s academic training and research experience have provided him with a broad background for the interrogation of developmental, pathological, and aging-related processes of the musculoskeletal system. He holds a German engineering diploma (Dipl.Ing., equals combined BS & MS) from TU Berlin and a master’s degree in Bioengineering from Dongseo University, South Korea. During his undergraduate studies at the Julius-Wolff-Institute for Biomechanics and Musculoskeletal Regeneration, Charité Berlin, he examined the effect of mechanical stimuli on lineage decisions of bone-resident stem cells.

The work in Dr. Kay Raum’s lab set the stage for his graduate research at the German Institute of Human Nutrition in the newly established lab of Dr. Tim J. Schulz earning him a Ph.D. from the University of Potsdam, Germany by delineating the developmental origin and function of bone marrow adipose tissue, becoming one of the pioneers in this research area. Initially supported by a two-year postdoctoral scholarship from the German Research Foundation, he conducted his postdoctoral training in the lab of Dr. Charles Chan at Stanford University where he later received a prestigious NIA/NIH K99/R00 Award to study skeletal stem cell biology with focus on aging.  

SSCs are found in distinct anatomical regions of bones with specialized functions contributing to the formation, maintenance, and repair of skeletal tissue. They can differentiate into osteoblasts (bone-forming cells), chondrocytes (cartilage-forming cells), and stromal cells. SSCs also generate specialized niches in the bone marrow that support the formation of blood cells. The interaction between SSCs and hematopoietic stem cells (HSCs) is essential for maintaining bone health as well as blood and immune cell production.       

Our research focuses on understanding the diversity, lineage dynamics, and differentiation trajectories of skeletal stem cells (SSCs) in both mice and humans. We aim to gain a comprehensive understanding of the cellular and molecular mechanisms that drive SSC behavior in health and disease. To achieve this goal, we employ a wide range of cutting-edge techniques, including single cell sequencing and clonal tracking, to study the diversity and lineage dynamics of SSC populations. Additionally, we use cellular barcoding techniques to track the behavior of individual cells and their descendants over time, providing a detailed view of SSC behavior during distinct perturbations. We are also exploring spatial transcriptomics to get a more comprehensive understanding of the exact cellular and molecular architecture in bone marrow niches generated by SSC lineage populations. Our long-term goal is to use this knowledge to develop new therapies and interventions that can prevent and reverse SSC-based aging and malignancies in both the skeletal and hematopoietic systems.

In contrast to “MSCs”, a highly heterogeneous cell population often interchangeably used for stromal cells found in a variety of tissues such as bone marrow, adipose tissue, and umbilical cord blood, SSCs are much better defined with a detailed lineage hierarchy. The impurity of “MSCs” strongly limits their use for the discovery of new biology and their translational application.   

The function of SSCs can be influenced by a variety of factors, including glucocorticoids, which are a class of steroid hormones that are involved in the regulation of various physiological processes, including the immune response and metabolism. Excessive or prolonged exposure to glucocorticoids can lead to bone loss, a condition known as glucocorticoid-induced osteoporosis (GIOP). We have identified a new SSC-derived molecule - Basigin, which seems to mediate detrimental skeletal-endothelial crosstalk during GIOP. We are now working to better understand the molecular and cellular underpinnings of this signaling axis as blocking it is sufficient to prevent GIOP and even reverse bone loss in aged osteoporotic mice. 

Endocrine interactions play an important role in the regulation of SSCs and bone health. The bone-brain axis, which refers to the connection between the skeleton and the central nervous system, is critical for the regulation of bone metabolism. The central regulation of bone is mediated by hormones and neurotransmitters, which interact with SSCs to modulate their behavior and function. Our collaborative work has identified a novel maternal brain hormone  (CCN3) that sustains bone mass during lactation by stimulating bone formation through SSCs. We are currently working to improve our understanding of the regulation of this hormone including the signaling mechanism in SSCs. This discovery might have broader implications, as it might be leveraged as a new urgently needed osteoanabolic drug.

Emerging studies highlight the diverse impacts of the gut microbiome on bone remodeling, influenced by age, sex, and bacterial composition. So far, microbiome research has broadly relied on association studies with little iterative approaches to reveal causal relationships. Skeletal and hematopoietic systems in the bone marrow (BM) are regulated by local and systemic factors, including those released by the gut microbiome. We are investigating the functional connection between age-related changes of gut metabolite production and SSC-mediated mechanism of the skeleton. 

Articular cartilage has very limited ability to regenerate and cartilage loss due to trauma or degenerative conditions often leads to irreversible joint damage. Osteoarthritis is one of the most common age-related diseases. Aside from joint replacement procedures alternative approaches for repairing tissue damage have revolved around methods to replace lost cartilage through grafting or stem cell therapy. We have developed a stem cell-targeted approach that can regenerate cartilage. Our approach has demonstrated efficacy in mouse, pig and human tissue. We are currently further optimizing the formulation of this one-step therapy and are pursuing translational avenues to bring it to the clinic. 

Osteosarcoma (OS) is the most common primary malignant tumor of bone. Most cases occur in children and adolescents with a peak incidence during the pubertal growth spurt. OS most commonly arises in anatomical subregions of skeletal sites that are inhabited by bone stem cells. Previous studies have provided evidence for the existence of OS cancer stem cells critical for tumor initiation, therapy resistance, recurrence and in some cases metastasis. However, the identity of the exact cell type of origin remains elusive. By studying OS through the lens of SSC biology and leveraging cutting-edge technology, we aim to overcome the challenges of treating this aggressive cancer and develop more effective, precise treatments that also target related metastases.

FUNDING: We are grateful for funding support by the National Institute of Health (NIH/NIA), the California Institute for Regenerative Medicine (CIRM), the W.F. Keck Foundation as well as UC Davis pilot and training grants.