Welcome to the Ambrosi Laboratory
Dr. Ambrosi'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.
Skeletal stem cells are in the front and center of our research endeavors. Research spans the continuum of basic to translational research. We use a combination of mouse models and human tissues to study the biology of SSCs in health and disease. Our research encompasses a wide range of leading-edge techniques, from flow cytometry to single cell omics and in vivo cellular barcoding to spatial transcriptomics, to gain a comprehensive understanding of the cellular and molecular mechanisms that govern SSC behavior.
Skeletal Stem Cell Diversity and Lineage Dynamics
This research direction 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, flow cytometry, transplantation assays, and in vivo clonal tracking, to study the diversity and lineage dynamics of SSC populations. Our cellular barcoding techniques allow us to track the behavior of individual cells and their descendants over time, gain functional insights one cell at a time with multiparameter readouts, thereby providing a detailed view of SSC behavior during distinct perturbations. We are also exploring spatial transcriptomics techniques to get a more comprehensive understanding of the exact cellular and molecular architecture of 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.
Mechanisms of Skeletal Stem Cell Dysfunction during Aging and Disease
Another big focus in our lab pertains to the understanding of the mechanistic underpinnings that drive an intrinsically aged state in SSCs, that we have shown to be detrimental to skeletal and hematopoietic health. SSCs reside in specialized microenvironments in the bone marrow, known as niches, which provide the necessary signaling cues that regulate the behavior of SSCs and the hematopoietic stem cells (HSCs) that reside alongside them. The composition of SSC niches, cellular architecture, and molecular crosstalk are essential for maintaining the balance between the formation of bone and blood cells. However, with aging and disease, these niches change. Our goal is to map changes in SSC niches during aging as well as to extend our efforts to gain new insight into the development of metastatic bone marrow niches and osteosarcomas.
Endocrine Interactions of the Skeletal Stem Cell System
Endocrine interactions play an important role in the regulation of SSCs and bone health. The function of SSCs is influenced by a variety of circulating factors. For example, glucocorticoids (GCs), a class of steroid hormones that are involved in the regulation of various physiological processes, including the immune response and metabolism, have a great impact on skeletal biology. Excessive or prolonged exposure to GCs can lead to bone loss, a condition known as glucocorticoid-induced osteoporosis (GIOP). We are trying to understand how SSC lineage dynamics and crosstalk to other bone-resident cell types are altered during chronic exposure to GCs. Additionally, we are studying the bone-brain axis, which refers to the connection between the skeleton and the central nervous system that 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. Together with our collaborators from the field of neuroscience we are elucidating new sex-specific factors released from the brain that drive high bone mass. This line of research could potentially reveal new anti-osteoporosis drug.
- ASBMR John Haddad Young Investigator Award, 2022
- Young Investigator Award of the ASBMR, 2021
- Young Investigator Travel & Merit Award of the ISSCR, 2021
- ASBMR pre-meeting Best Scientific Oral Presentation Award, 2020
- Travel & Best Oral Presentation Award of the Bone Marrow Adiposity Society, 2019
- Young Investigator Travel & Merit Award of the ISSCR, 2019
- German Research Foundation (DFG) Postdoc Abroad Scholarship (2-year), 2018
- Ph.D. Thesis Award, Berlin School of Regenerative Medicine (BSRT), Charité Berlin, 2017
- Michelson-Award, University of Potsdam Best Dissertation 2016/17 Award, 2017
- German Academic Exchange Service (DAAD) Full Scholarship to Study Abroad, 2010
- The American Society for Bone and Mineral Research (ASBMR)
- International Society for Stem Cell Research (ISSCR)
- BoneMarrow Adiposity Society (BMAS)
Click here to find a complete list of publications.
- Ambrosi TH, Chan CKF. A Seed-and-Soil Theory for Blood Ageing. Nature Cell Biology. 2023 doi: https://doi.org/10.1038/s41556-022-01062-z.
- Butler MGK, Ambrosi TH, Murphy MP, Chan CKF. Aging of Skeletal Stem Cells. Adv Geriatr Med Res. 2022;4(2):e220006. doi: https://doi.org/10.20900/agmr20220006.
- Andrew TW, Koepke LS, Wang Y, Lopez M, Steininger H, Struck D, Boyko T, Ambrosi TH, Tong X, Sun Y, Gulati GS, Murphy MP, Marecic O, Telvin R, Schallmoser K, Strunk D, Seita J, Goodman SB, Yang F, Longaker MT, Yang GP & Chan CKF. Sexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration. Nature Communications. 2022 Oct 30. doi: 1038/s41467-022-34063-5 . PMID: 36310174 .
- Goodnough LH, Ambrosi TH*, Steininger HM, Hoover MY, Choo H, Van Rysselberghe NL, Bellino MJ, Bishop JA, Gardner MJ, Chan CKF. Cross-species comparisons reveal unexpected resistance of human skeletal stem cells to inhibition by non-steroidal anti-inflammatory drugs. Frontiers in Endocrinology. 2022 Aug 25. doi: 10.3389/fendo.2022.924927. PMID: 36093067. *co-first author.
- Ambrosi TH, Chan CKF. Bone Marrow Niche: Skeletal Stem Cells as the Developmental Origin of Cellular Niches for Hematopoietic Stem and Progenitor Cells. Curr Top Microbiol Immunol.2021;434:1-31. doi: 10.1007/978-3-030-86016-5_1. PMID: 34850280.
- Ambrosi TH, Marecic O, McArdle A, Sinha R, Gulati GS, Tong X, Wang Y, Steininger HM, Hoover MY, Koepke LS, Murphy MP, Sokol J, Seo E, Tevlin R, Lopez M, Conley SD, Brewer RE, Mascharak S, Lu L, Ajanaku O, Seita J, Sahoo D, Yang F, Weissman IL, Longaker MTL, Chan CKF. Aged skeletal stem cells generate an inflammatory degenerative niche. 2021 Aug 11. doi: 10.1038/s41586-021-03795-7. PMID: 34381212.
- Ambrosi TH, Sinha R, Steininger HM, Hoover MY, Murphy MP, Koepke LS, Wang Y, Conley S, Weissman IL, Longaker MT, Chan CKF. Distinct skeletal stem cell types orchestrate long bone skeletogenesis. Elife. 2021 Jul 19;10:e660. doi: 10.7554/eLife.66063. PMID: 34280086.
- Ambrosi TH, Goodnough LH, Chan CKF. Human skeletal stem cell aging. Aging (Albany NY). 2020 Sep 14;12(17):16669-16671. doi: 10.18632/aging.104034. PMID: 32929053.
- Goodnough LH, Ambrosi TH*, Steininger HM, DeBaun MR, Abrams GD, McAdams TR, Gardner MJ, Chan CKF, Bishop JA. Delayed Union of a Diaphyseal Forearm Fracture Associated With Impaired Osteogenic Differentiation of Prospectively Isolated Human Skeletal Stem Cells. JBMR Plus. 2020 Aug 31;4(10):e10398. doi: 10.1002/jbm4.10398. PMID: 33103027. *co-first author.
- Murphy MP, Koepke LS, Lopez MT, Tong X, Ambrosi TH, Gulati GS, Marecic O, Wang Y, Ransom RC, Hoover MY, Steininger H, Zhao L, Walkiewicz MP, Quarto N, Levi B, Wan DC, Weissman IL, Goodman SB, Yang F, Longaker MT, Chan CKF. Articular cartilage regeneration by activated skeletal stem cells. Nature Medicine. 2020 Aug 17;. doi: 10.1038/s41591-020-1013-2. PMID: 32807933.
- Ambrosi TH, Goodnough LH, Steininger HM, Hoover MY, Kim E, Koepke LS, Marecic O, Zhao L, Seita J, Bishop JA, Gardner MJ, Chan CKF. Geriatric fragility fractures are associated with a human skeletal stem cell defect. Aging Cell. 2020 Jul;19(7):e13164. doi: 10.1111/acel.13164. PMID: 32537886.
- McNulty MA, Goupil BA, Albarado DC, Castaño-Martinez T, Ambrosi TH, Puh S, Schulz TJ, Schürmann A, Morrison CD, Laeger T. FGF21, not GCN2, influences bone morphology due to dietary protein restrictions. Bone Rep. 2020 Jun;12:100241. doi: 10.1016/j.bonr.2019.100241. PMID: 31921941.
2019 and earlier
- Ambrosi TH, Longaker MT, Chan CKF. A Revised Perspective of Skeletal Stem Cell Biology. Front Cell Dev Biol. 2019;7:189. doi: 10.3389/fcell.2019.00189. PMID: 31572721.
- Graja A, Garcia-Carrizo F, Jank AM, Gohlke S, Ambrosi TH, Jonas W, Ussar S, Kern M, Schürmann A, Aleksandrova K, Blüher M, Schulz TJ. Loss of periostin occurs in aging adipose tissue of mice and its genetic ablation impairs adipose tissue lipid metabolism. Aging Cell. 2018 Oct;17(5):e12810. doi: 10.1111/acel.12810. PMID: 30088333.
- Chan CKF, Gulati GS, Sinha R, Tompkins JV, Lopez M, Carter AC, Ransom RC, Reinisch A, Wearda T, Murphy M, Brewer RE, Koepke LS, Marecic O, Manjunath A, Seo EY, Leavitt T, Lu WJ, Nguyen A, Conley SD, Salhotra A, Ambrosi TH, Borrelli MR, Siebel T, Chan K, Schallmoser K, Seita J, Sahoo D, Goodnough H, Bishop J, Gardner M, Majeti R, Wan DC, Goodman S, Weissman IL, Chang HY, Longaker MT. Identification of the Human Skeletal Stem Cell. Cell. 2018 Sep 20;175(1):43-56.e21. doi: 10.1016/j.cell.2018.07.029. PMID: 30241615.
- Tolkachov A, Fischer C, Ambrosi TH, Bothe M, Han CT, Muenzner M, Mathia S, Salminen M, Seifert G, Thiele M, Duda GN, Meijsing SH, Sauer S, Schulz TJ, Schupp M. Loss of the Hematopoietic Stem Cell Factor GATA2 in the Osteogenic Lineage Impairs Trabecularization and Mechanical Strength of Bone. Mol Cell Biol. 2018 Jun 15;38(12). doi: 10.1128/MCB.00599-17. PMID: 29581184.
- Ambrosi TH, Scialdone A, Graja A, Gohlke S, Jank AM, Bocian C, Woelk L, Fan H, Logan DW, Schürmann A, Saraiva LR, Schulz TJ. Adipocyte Accumulation in the Bone Marrow during Obesity and Aging Impairs Stem Cell-Based Hematopoietic and Bone Regeneration. Cell Stem Cell. 2017 Jun 1;20(6):771-784.e6. doi: 10.1016/j.stem.2017.02.009. PMID: 28330582.
- Ost M, Coleman V, Voigt A, van Schothorst EM, Keipert S, van der Stelt I, Ringel S, Graja A, Ambrosi T, Kipp AP, Jastroch M, Schulz TJ, Keijer J, Klaus S. Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action. Mol Metab. 2016 Feb;5(2):79-90. doi: 10.1016/j.molmet.2015.11.002. PMID: 26909316.
- Puts R, Ruschke K, Ambrosi TH, Kadow-Romacker A, Knaus P, Jenderka KV, Raum K. A Focused Low-Intensity Pulsed Ultrasound (FLIPUS) System for Cell Stimulation: Physical and Biological Proof of IEEE Trans Ultrason Ferroelectr Freq Control. 2016 Jan;63(1):91-100. doi: 10.1109/TUFFC.2015.2498042. PMID: 26552085.
- Ambrosi TH, Schulz TJ. The emerging role of bone marrow adipose tissue in bone health and dysfunction. J Mol Med (Berl). 2017 Dec;95(12):1291-1301. doi: 10.1007/s00109-017-1604-7. PMID: 29101431.