Nahrendorf Lab

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Phone: 617-643-3242

The Nahrendorf laboratory focuses on the role of immunity in cardiovascular health and disease, specifically in atherosclerosis and heart failure. Of particular interest are the function, supply and production of leukocytes, and the signals that regulate hematopoiesis after injuries such as myocardial infarction or stroke. We described that after MI, the spleen releases a large population of ready-made leukocytes that travel to the ischemic heart (Science 2009, New York Times 2009). We further found that MI, chronic stress and sedentary life style modulate the hematopoietic stem cell niche, activating migration and proliferation of myeloid progenitor cells (Nature 2012, Nature Med 2014, Nature Med 2019). Resident macrophages, on the other hand, do not derive from circulating cells and promote steady state functions such as cardiac conduction (Cell 2017). The laboratory also develops and employs imaging to sample biology non-invasively, using MR, nuclear, optical and microscopic modalities.

Recent Publications

  • Hegemann N, Sang P, Kim JH, Koçana C, Momin N, Klages J, Kucherenko MM, Knosalla C, O'Brien B, Simmons S, Nahrendorf M, Kuebler WM, Grune J Ultrasonographic assessment of pulmonary and central venous congestion in experimental heart failure. Am J Physiol Heart Circ Physiol. 2023;326(2):H433-H440 - PMID: 38099848 - DOI: 10.1152/ajpheart.00735.2023

  • Zhang S, Paccalet A, Rohde D, Cremer S, Hulsmans M, Lee IH, Mentkowski K, Grune J, Schloss MJ, Honold L, Iwamoto Y, Zheng Y, Bredella MA, Buckless C, Ghoshhajra B, Thondapu V, van der Laan AM, Piek JJ, Niessen HWM, Pallante F, Carnevale R, Perrotta S, Carnevale D, Iborra-Egea O, Muñoz-Guijosa C, Galvez-Monton C, Bayes-Genis A, Vidoudez C, Trauger SA, Scadden D, Swirski FK, Moskowitz MA, Naxerova K, Nahrendorf M Bone marrow adipocytes fuel emergency hematopoiesis after myocardial infarction. Nat Cardiovasc Res. 2023;2(12):1277-1290 - PMID: 38344689 - PMCID: PMC10857823 - DOI: 10.1038/s44161-023-00388-7

  • Mazzitelli JA, Pulous FE, Smyth LCD, Kaya Z, Rustenhoven J, Moskowitz MA, Kipnis J, Nahrendorf M Skull bone marrow channels as immune gateways to the central nervous system. Nat Neurosci. 2023;26(12):2052-2062 - PMID: 37996526 - PMCID: PMC10894464 - DOI: 10.1038/s41593-023-01487-1

  • Gustafsson K, Rhee C, Frodermann V, Scadden EW, Li D, Iwamoto Y, Palchaudhuri R, Hyzy S, Boitano A, Nahrendorf M, Scadden DT Clearing and replacing tissue-resident myeloid cells with an anti-CD45-antibody-drug conjugate. Blood Adv. 2023;7(22):6964-6973 - PMID: 37748049 - PMCID: PMC10690556 - DOI: 10.1182/bloodadvances.2023010561

  • Gustafsson K, Rhee C, Frodermann V, Scadden EW, Li D, Iwamoto Y, Palchaudhuri R, Hyzy SL, Boitano AE, Nahrendorf M, Scadden DT CD45-antibody-drug conjugate clears tissue resident myeloid cells from their niches enabling therapeutic adoptive cell transfer. bioRxiv. 2023;:ePub - PMID: 37732224 - PMCID: PMC10508759 - DOI: 10.1101/2023.09.05.556397

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Research projects

Leukocytes in cardiovascular health

The Nahrendorf laboratory shares a longstanding interest with the Swirski lab in innate immune cells, especially myeloid cells. We discovered that healing after myocardial infarction involves time-resolved monocyte and macrophage subset dynamics. We identified a splenic monocyte reservoir, which deploys within 24 hours after myocardial infarction. This reservoir contributes half of all monocytes recruited to the infarct. In atherosclerosis and chronic heart failure, macrophages expand by proliferating locally, and there is interaction between local and systemic inflammation, including in the remote myocardium after ischemic injury. In the healthy heart, cardiac resident macrophages connect to myocytes via gap junctions and participate in electric conduction; their depletion leads to conduction abnormalities such as AV block.

Activation of hematopoiesis in cardiovascular disease

We described the mechanisms behind acceleration of atherosclerotic disease after a first infarct in the heart or brain. Infarct-induced sympathetic nervous system signaling in the bone marrow activates hematopoietic stem cells, which begin to proliferate and relocate to the spleen where they over-produce leukocytes. The most upstream point of hematopoiesis activation rests in CCR2+ hematopoietic stem cells. Newly produced leukocytes migrate to the atherosclerotic plaque, rendering it more inflamed and vulnerable to rupture, triggering reinfarction, a frequent clinical event that was previously unexplained. The findings are clinically important as they provide a new therapeutic opportunity to prevent secondary complications of atherosclerosis. We subsequently observed similar pathway activation after ischemic stroke and during exposure to chronic psychosocial stress.

In vivo RNAi for immunomodulation

In collaboration with MIT and Alnylam, we pioneered in vivo RNAi to silence the chemokine receptor CCR2, and subsequently other targets, in monocytes, macrophages and endothelial cells. Delivered by nanoparticles, siRNA is incorporated into splenic and circulating monocytes and macrophages, resulting in efficient silencing of gene expression. These cells 'lose their GPS', i.e. they are no longer able to migrate to the site of inflammation. This new class of anti-inflammatory therapy is highly selective, as it only targets certain genes. Subsequently we have targeted other proteins in myeloid cells and their progenitors as well as endothelial cells.

News

2022-03-07:

Kamila Naxerova, PhD received the 2022 Howard Goodman Fellowship Awards. The project is titled “Defining the Evolutionary Characteristics of Human Metastasis Across Space and Time.” The Goodman Award is an endowed fellowship established by the MGH Department of Molecular Biology in honor of its founding chief, Howard M. Goodman, PhD

2021-03-05:

Dr.
Moskowitz, associate faculty at the Center for Systems Biology, won the 2021 Brain Prize!

Mike's groundbreaking work on the trigeminovascular system paved the way to the development of an entirely new class of migraine-specific drugs called CGRP antagonists which help provide long-term prevention of migraine attacks.

Micheal Moskowitz and three other neuroscientists are sharing the world’s most prestigious prize for brain research which is awarded annually by the Lundbeck Foundation.

2020-09-14:

The Nutrition Obesity Research Center at Harvard (NORCH) and the Metabolism Unit at MGH have selected Maarten Hulsmans (Nahrendorf Lab) and his project “Resolving macrophage heterogeneity of human atrial remodeling at single-cell level” to receive 2020-2021 NORCH Pilot & Feasibility Awards.

2020-01-10:

The exercise manuscript by Frodermann and Rohde (Nahrendorf Lab) received the 2020 MGH Martin Prize in Clinical Research. Bottom line: get your recommended 150 min of exercise per week!

2019-12-12:

Matthias Nahrendorf has received the 2020 Rolf Sammet Guest Professorship at Frankfurt University. The professorship is dedicated to internationally outstanding scientists who have made important contributions in the life science and natural science fields. Nahrendorf was selected for his excellent work on links between the bone marrow and immune cells with cardiovascular disease.