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Principal Investigator: Charles KF Chan
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $500,000
Funding agency: National Institute on Aging
PROJECT SUMMARY/ABSTRACT
This proposal’s objective is to determine whether changing the signaling patterns between the skeletal stem
cells (SSCs) and hematopoietic stem cells (HSCs) can treat atherosclerotic cardiovascular disease (ASCVD).
Previous data from our lab suggests that aging SSCs can cause HSC inflammaging, defined as a skewing of
HSC progeny toward myeloid lineages that may be more dysfunctional, leading to the development of vascular
disease. Whether rejuvenating the SSCs can be used as a therapy in ASCVD remains unclear. Our long-term
goal is to develop novel therapy to reverse age-related ASCVD. Our central hypothesis is that the SSC
rejuvenation will rebalance HSCs and improve the function of their progeny that travel to the
vasculature in response to injury, preventing the progression of atherosclerosis. The rationale is that
previous work by our labs and others: 1) identified and characterized the existence of SSCs in mice and
humans, 2) demonstrated that transplantation of SSCs from aged mice cause inflammaging of HSCs in young
mice, 3) showed that HSC inflammaging contributes to ASCVD, and 4) observed that activated immune cells,
some of which originate from HSCs, contribute to plaque progression. Our work will enhance the understanding
of the cross talk between organs that contribute to ASCVD, paving the way for the development of novel
strategies for disease treatment. To test our central hypothesis and attain our objective, we propose the
following aims: 1. To characterize the effects of SSC aging on the vasculature (including the perivascular
fat). We hypothesize that aged SSCs skew HSCs toward dysfunctional myeloid progeny that promote ASCVD.
For this aim, we will first perform lineage tracing experiments. The expected outcome from the lineage tracing
experiments is that older mice with atherosclerosis have the highest proportion of HSC-progeny in their
vasculature. In our second set of experiments for Aim 1, we will determine whether HSC inflammaging induced
by aged SSCs contributes to atherosclerosis progression. We hypothesize that 2-month HSCs transplanted
into 20-month mice become aged and their progeny then cause atherosclerotic progression in pro-atherogenic
mice fed a high fat diet. We will perform cell transplantation studies to determine whether exposure to youthful
or aged SSCs affects atherosclerotic progression. We expect that young HSCs exposed to aged SSCs will
develop HSC inflammaging and contribute to plaque progression. Finally, we will compare the proteomic and
genomic signatures of these multiple organs in humans to confirm that SSC aging also contributes to human
atherosclerosis. 2. To determine whether targeted reversal of age-related decreases in BMP2 signaling
in SSCs can alter atherosclerosis progression. We hypothesize that BMP2 infusion or application of a BMP2
infused hydrogel to aged bones creates a more balanced HSC progeny, decreasing vascular inflammation and
preventing the progression of ASCVD. We will perform a randomized, control trial of local BMP2 treatment into
the bone marrow and measure its effects on plaque size and composition.
Terms: <0-11 years old><21+ years old><6 year old><6 years of age><Adult><Adult Human><Affect><Aging><Animal Model><Animal Models and Related Studies><Apoplexy><Area><Arteries><Assay><Atherosclerosis><Atherosclerotic Cardiovascular Disease><BMP-2><BMP-2A><BMP2><BMP2 gene><BMP2A Gene><Basic Research><Basic Science><Bioassay><Biological Assay><Blood Precursor Cell><Blood Vessels><Body System><Bone Marrow><Bone Marrow Reticuloendothelial System><Bone Morphogenetic Protein 2 Gene><Bone Morphogenetic Protein 2A Gene><Brain Vascular Accident><Cardiac infarction><Cell Body><Cell Communication and Signaling><Cell Differentiation><Cell Differentiation process><Cell Signaling><Cell Transplantation><Cells><Cellular Assay><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Cessation of life><Child><Child Youth><Children (0-21)><Data><Death><Development><Disease><Disorder><Environment><Equilibrium><Exposure to><Fats><Fatty acid glycerol esters><Food><Funding><Goals><Government><HSC transplantation><Hematopoietic Progenitor Cells><Hematopoietic Stem Cell Transplant><Hematopoietic Stem Cell Transplantation><Hematopoietic stem cells><High Fat Diet><Histology><Homelessness><Human><Hydrogels><Immune><Immune system><Immunes><In Vitro><Individual><Inflammaging><Infusion><Infusion procedures><Intracellular Communication and Signaling><Investigators><Ischemic Heart><Ischemic Heart Disease><Ischemic myocardium><LDL><LDL Lipoproteins><Learning><Left><Low-Density Lipoproteins><Measures><Mice><Mice Mammals><Microscopy><Modern Man><Murine><Mus><Myelogenous><Myeloid><Myocardial Infarct><Myocardial Infarction><Myocardial Ischemia><Non-Polyadenylated RNA><Organ><Organ System><Outcome><Patients><Pattern><Phagocytosis><Physicians><Placebos><Productivity><Protein Secretion><RNA><RNA Gene Products><Randomized><Refugee Camp><Refugees><Rejuvenation><Reporter><Research><Research Personnel><Researchers><Ribonucleic Acid><Risk><Scientist><Sham Treatment><Signal Transduction><Signal Transduction Systems><Signaling><Societies><Staining method><Stains><Stroke><System><Techniques><Testing><Tissue Harvesting><Translational Research><Translational Science><Transplantation><Travel><Vascular Diseases><Vascular Disorder><Vascular blood supply><Viet Nam><Vietnam><War><Work><Wound Repair><adulthood><age 6 years><age associated><age associated alterations><age associated changes><age associated effects><age correlated><age correlated alterations><age correlated changes><age dependent><age dependent alterations><age dependent changes><age effect><age linked><age related><age related alterations><age related changes><age related effects><age specific><age specific alterations><age specific changes><age-related inflammation><aged><aged bone><aged mice><aged mouse><aging effect><aging reversal><alterations with age><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><balance><balance function><beta-Lipoproteins><biological signal transduction><blood cell progenitor><blood progenitor><blood stem cell><blood supply><blood vessel disorder><blood-forming stem cell><bone aging><bone morphogenetic protein 2><brain attack><cardiac infarct><cardiac ischemia><career><cell assay><cellular differentiation><cellular transplant><cerebral vascular accident><cerebrovascular accident><changes with age><chronic inflammatory disease><control trial><coronary attack><coronary infarct><coronary infarction><coronary ischemia><cytokine><developmental><disadvantaged background><elderly mice><elderly patient><experiment><experimental research><experimental study><experiments><feeding><functional improvement><genomic classifier><genomic signature><heart attack><heart infarct><heart infarction><heart ischemia><hematopoietic cell transplantation><hematopoietic cellular transplantation><hematopoietic progenitor><hematopoietic progenitor cell transplantation><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><homeless><human tissue><impact of age><improve function><improved functional outcomes><inflamm-ageing><inflamm-aging><influence of age><infusions><injury response><kids><life span><lifespan><marginalized background><migration><model of animal><multidisciplinary><myocardial ischemia/hypoxia><myocardium ischemia><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><old mice><older patient><prevent><preventing><progenitor aging><progenitor cell aging><proteomic signature><randomisation><randomization><randomly assigned><response to injury><reverse aging><reverse aging effects><reversible aging><sham therapy><six year old><six years of age><skeletal progenitor><skeletal progenitor cell><skeletal stem cell><stem cell aging><stroked><strokes><success><therapeutic target><translation research><translational investigation><transplant><unhoused><uptake><vascular><vascular dysfunction><vascular inflammation><vascular supply><vasculopathy><western diet><western-style diet><western-type diet><wound healing><wound recovery><wound resolution><youngster>