Regenerative medicine holds immense promise for treating damaged and diseased tissues. One way to achieve this goal is to identify tissue-specific stem cells, which when introduced into organs, will stimulate regeneration. Alternatively, identification of triggers that stimulate tissue-specific progenitor cells will lead to development of small molecules or biologics to enhance the endogenous programs of tissue regeneration. Although experimental support exists for both therapeutic strategies, the molecular signals that trigger regenerative processes remain largely unknown. Although activation of the immune system, a universal response to injury, is a good candidate for triggering the tissue regeneration, the molecular pathways that directly link the immune system to progenitor cell biology remain poorly understood. We hypothesize that the ability of macrophages to penetrate tissue sites, integrate environmental inputs and transmit regenerative signals ideally positions these cells to be the central orchestrators of the regenerative response. In this model, recruited macrophages would form a mobile niche for tissue-specific progenitor cells, performing pleiotropic functions via enactment of distinct activation programs in spatially- and temporally-defined manner. Consistent with this view, our preliminary data show that deployment and activation of macrophages is essential for coordinating tissue regeneration after injury, including clearance of debris, activation and proliferation of tissue-specific stem cells, and differentiation of committed progenitors. Thus, the NIH Director's Pioneer Award Program will allow me to test the universality of these findings and to delineate molecular pathways for stimulating the endogenous programs of tissue regeneration, studies which collectively will be transformative for the field of regenerative medicine. Public Health Relevance Macrophages, the sentinels of host defense, are also the first cells to be recruited to site

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
8DP1AR064158-05
Application #
8299034
Study Section
Special Emphasis Panel (ZGM1-NDPA-B (02))
Program Officer
Nuckolls, Glen H
Project Start
2009-09-30
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$764,775
Indirect Cost
$269,775
Name
University of California San Francisco
Department
Physiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Ganeshan, Kirthana; Chawla, Ajay (2014) Metabolic regulation of immune responses. Annu Rev Immunol 32:609-34
Mauer, Jan; Chaurasia, Bhagirath; Goldau, Julia et al. (2014) Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol 15:423-30
Qiu, Yifu; Nguyen, Khoa D; Odegaard, Justin I et al. (2014) Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157:1292-308
Goh, Y P Sharon; Henderson, Neil C; Heredia, Jose E et al. (2013) Eosinophils secrete IL-4 to facilitate liver regeneration. Proc Natl Acad Sci U S A 110:9914-9
Nussbaum, Jesse C; Van Dyken, Steven J; von Moltke, Jakob et al. (2013) Type 2 innate lymphoid cells control eosinophil homeostasis. Nature 502:245-8
Odegaard, Justin I; Chawla, Ajay (2013) The immune system as a sensor of the metabolic state. Immunity 38:644-54
Odegaard, Justin I; Chawla, Ajay (2013) Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science 339:172-7
Odegaard, Justin I; Ganeshan, Kirthana; Chawla, Ajay (2013) Adipose tissue macrophages: Amicus adipem? Cell Metab 18:767-8
Eisele, Nicholas A; Ruby, Thomas; Jacobson, Amanda et al. (2013) Salmonella require the fatty acid regulator PPARýý for the establishment of a metabolic environment essential for long-term persistence. Cell Host Microbe 14:171-82
Heredia, Jose E; Mukundan, Lata; Chen, Francis M et al. (2013) Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration. Cell 153:376-88

Showing the most recent 10 out of 14 publications