The ability of tissues to grow to their proper size during development and sustain cell renewal after tissue damage is critical to the maintenance of organ function throughout life. Substantial evidence indicates that loss of tissue resident myeloid cells blunts both physiologic organ?s growth and tissues regenerative potential in aging and after injury. However, the specific myeloid subsets and signaling cues driving such growth effects in different anatomic locations remain unknown. This proposal aims to fill this gap in knowledge by testing the central hypothesis that organ and/or age-specific tissue growth and regenerative potential reflects the recruitment, expansion and/or functional specialization of select myeloid populations. Using the endocrine compartment of the pancreas as a tissue model system endowed with age-restricted proliferative capacity, our previous work identifies CCR2+ myeloid cells as well as granulocytes as regulators of pancreatic islets proliferation in peri-natal life and after injury in vivo. Furthermore, we provide evidence for a role of myeloid-derived adenosine signaling in islet regenerative responses, pointing to myeloid cells as novel targets to convey therapeutic modulation of this pathway to sites of tissue repair. Using this tissue model, we will address our hypothesis in the following aims: 1) Determine the requirement of CCR2+ myeloid cells and granulocytes in islet cell proliferation, using models of myeloid cell subset-specific ablation, adoptive transfer and functional skewing. 2) Determine the functional impact of adenosine signaling on islet proliferation using loss and gain-of function models of this signaling pathway. While providing critical mechanistic insights on the functional diversity of myeloid cells populating tissues during development, homeostasis and regeneration, these studies may lead to novel therapeutic strategies aiming at restoring tissue function following degenerative processes associated with aging and/or injury.
Degenerative diseases such as diabetes mellitus are severely debilitating diseases that would significantly benefit from new tissue regenerative treatments. In this proposal we investigate how specialized cells of the innate immunity residing in the pancreas could be manipulated to trigger and sustain pro-regenerative functions on injured pancreatic islet cells. This line of work holds significant translational value as it may lead to the use of myeloid cell therapies to support tissue regeneration.
