Regenerative Medicine

Dr. Hambright is a Principal Investigator and Program Director at the Linda and Mitch Hart Center for Regenerative and Personalized Medicine (CRPM) at Steadman Philippon Research Institute (SPRI). He received his BS in Biology from the University of Texas at Tyler. He then completed his MS in Microbiology at the University of Texas at Arlington prior to completing his PhD training in the Biology of Aging Training Program at UTHealth San Antonio at the Barshop Institute for Longevity and Aging Studies. As a PhD student under Qitao Ran, he investigated the redox biology of age-associated neurodegenerative diseases including mechanisms related to aberrant lipid peroxidation and cognitive decline. He and his colleagues were the first to identify ferroptosis as a novel cell-death mechanism responsible for degeneration of neurons primarily afflicted during ALS and Alzheimer’s disease. His work elucidating these mechanisms in different neuronal populations has garnered over 500 citations from two different manuscripts.

At SPRI, Dr. Hambright’s focus is to develop strategies that target fundamental properties of aging including senescent (aged) cell accumulation, telomere erosion, and inflammation to improve orthoregenerative medicine therapies. He investigates interventions that encompass four primary pillars: exercise, diet, stem-cell-based therapies, and anti-aging compounds including senolytic drugs. He coordinates basic science projects in the CRPM and helps design and initiate clinical studies targeting age-related diseases such as osteoarthritis and osteoporosis through The Steadman Clinic. In this role, he helps translate aging-related pre-clinical findings to the clinic by negotiating the regulatory and scientific challenges that exist between. His overarching goal is to provide a combinatorial treatment approach targeting these pillars to improve healthy aging and restore active living.

Current Grants:

1. NIH1UG3AR077748-01 | Principal Investigator: Huard | 8/1/2020-7/31/25
   
   Project Title: “The Use of Senolytic and Anti-Fibrotic Agents to Improve the Beneficial Effect of Bone Marrow Stem Cells for Osteoarthritis”
   Role: Co-Investigator
    
2. DOD N00014-18-RFI-0014 | Principal Investigator: Huard | 0/01/19 - 9/30/22
   
   Project Title: “Response to the Treatment of Poly-Traumatic Injuries Using Platelet-Rich Plasma and Bone Marrow Concentrate: Prospective Evaluation of Platelet-Rich Plasma and Bone Marrow Concentrate Treatment to Accelerate Healing After Anterior Cruciate Ligament Reconstruction”
   Role: Co-Investigator
    
3. DOD N00014-18-RFI-0014 | Principal Investigator: Huard | 10/01/19 - 9/30/22
   
   Project Title: “Response to the Treatment of Poly-Traumatic Injuries Using Platelet-Rich Plasma and Bone Marrow Concentrate: Senolytic Drugs Attenuate Osteoarthritis-Related Articular Cartilage Degeneration: A Clinical Trial”
   Role: Co-Investigator

Prior support:

1. T32 AG021890 | N. Musi (PI) | 09/01/13-06/01/17
   The primary goal of the proposed Training Program is to prepare both graduate students and postdoctoral fellows for careers as independent investigators in the biology of aging.
   Role: Predoctoral Trainee
    
2. UTHealth Houston, Consortium on Aging Fellowship Stipend, WS Hambright (PI), 07/1/17-02/01/19
   This was a merit-based stipend awarded to postdoctoral fellows whose research involved the basic biology of aging and identifying novel treatment strategies for geronotological diseases. I was the inaugural recipient of this award.
   Role: Postdoctoral Fellow    

Honors and Awards:

• 2020: New Investigator Recognition Award (NIRA) Finalist, ORS Annual Meeting
• 2020: Travel Award Recipient from ORS to attend Annual Meeting
• 2017: Awarded Joe and Bettie Ward prize for Aging Research
• 2017: Awarded Fellowship Stipend Support from UTHealth Houston Consortium on Aging
• 2016: Awarded Travel Grant from Graduate School of Biomedical Sciences to Present at Cold Spring Harbor Neurodegeneration Annual Meeting, Long Island NY
• 2016: Travel Award Recipient from SfRBM for Oral Presentation at Annual Meeting, San Francisco CA
• 2016: Travel Award Recipient (FASEB) for Postdoctoral Preparation Institute, Bethesda MD
• 2015: Travel Award Recipient from Gordon Research Conferences to Present at Oxidative Stress and Disease Meeting, Ventura CA
• 2013: Awarded National Institute on Aging predoctoral training grant (T32AG021890)
• 2013: Elected as Student Representative, Cell Systems and Anatomy Committee of Graduate Studies (COGS)
• 2010: American Society for Microbiology National Meeting Travel Grant Recipient, San Diego CA
• 2010: UT Arlington Graduate Student Senate Travel Award Recipient to present at the American Society for Microbiology National Meeting, San Diego CA
• 2010: Phi Sigma Biology Graduate Student Honor Society Travel Grant Recipient
• 2004: Elected as President of Tri-Beta Biological Honor Society (UT Tyler chapter)

Contributions to Science:

Senotherapeutic drugs to treat age-associated orthopaedic decline:
An overarching goal of the Healthy Aging team is to develop translationally relevant therapies or diagnostics that improve musculoskeletal health during aging. A primary treatment modality we study is the use of senolytic agents, or drugs that selectively target and eliminate senescent cells. Senescent cells are strongly correlated with tissue decline during aging and contribute to chronic inflammation that promotes pathology. We use a variety of senolytic drugs both preclinically and clinically in federally funded trials to investigate their efficacy in orthopaedic conditions.

1. Naomasa Fukase, Ingrid K. Stake, Yoichi Murata, William S. Hambright, Sudheer Ravuri, Marc J. Philippon, Johnny Huard. “Interventional Strategies to Delay Aging-Related Dysfunction of the Musculoskeletal System” Intech Open. 2021 *In Press.
2. Hambright WS, Yeargan A, Whitney K, Montgomery B, Philippon M, Evans T, Hellwinkel J, Buckwalter J, Peault B & Huard J. “Potential Disease-Modifying Treatment Strategies in the Setting of Osteoarthritis”. OROAJ. 2021 *In Press
3. Mitchell J, Hambright WS, Whitney KE, Eck A, Evans TA, Huard J, “Joint Homeostasis: Cell and biologic factors contributing to health and decline with aging or trauma” ISAKOS. 2020
4. Verena Oberlohr, Haylie Lengel, William S. Hambright, Kaitlyn E. Whitney, Thos A. Evans, Johnny Huard, “Biologics for Skeletal Muscle Healing: The Role of Senescence and Platelet-Based Treatment Modalities” OTSM. 2020 https://doi.org/10.1016/j.otsm.2020.150754
5. Hambright WS, Huard J and Philippon M. “Rapamycin for Aging Stem Cells” AGING Journal. 2020. PMC7467370
6. Xiaodong Mu, Chi-Yi Lin, Hambright WS, Ying Tang, Polina Matre, Wanqun Chen, Xueqin Gao, Yan Cui, Ling Zhong, Bing Wang, and Johnny Huard. “Aberrant RhoA activation in macrophages increases senescence-associated secretory phenotypes and ectopic calcification in muscular dystrophic mice” AGING. 2020. PMC7803538

Selected Posters and Talks:

1. Heidi Kloser, Michael Mullen, John Mitchell, William S. Hambright, Sudheer Ravuri, Johnny Huard. “Naturally Occurring Flavonoids Attenuate Senescence in Human Banked Adipose-Derived Stem Cells.” (Poster) ORS Annual Meeting 2021
2. Hambright WS, Kawakami Y, Mu X, Gao X, Lu A, Eck A, Kirkland J, and Huard J. “The phytonutrient fisetin mitigates age-associated bone density loss in the Zmpste24-/- progeria mouse model.” (Poster) Experimental Biology General Meeting, San Diego CA, 2020.
3. John Mitchell, William S. Hambright, Michael Mullen, Anna Laura Nelson, Charles Huard, Sudheer Ravuri, Matthew Potter, and Johnny Huard. “Senotherapeutic Potential of the Anti-helminthic drug Niclosamide in Cultured Adipose Derived Stem Cells (ADSC) from Aged Human Donors.” (Poster) ORS General Meeting, Phoenix, AZ, 2020
4. Hambright WS, Mu X, Kawakami Y, Lu A, Cooke J, Huard J. “Alternative strategies to target age-associated osteoarthritis.” (Poster) Vail Scientific Summit, Vail, CO. 2018

Accelerated Aging (progeria) mouse models to study age related pathologies: Using murine models to recapitulate advanced age offers a practical preclinical tool to better understand the deleterious effects of aging. In our lab, we routinely utilize the Zmpste24-/- progeria model to investigate musculoskeletal decline and stem cell dysfunction with age, and to test senotherapies for the treatment of various orthopaedic conditions observed in Zmpste24-/- mice. Results using this model have provided key translatable data for the development and execution of two current Department of Defense (DoD)-funded clinical trials investigating biologics in the setting of ACL repair (NCT04205656) and senolytic drugs in the setting of knee osteoarthritis (NCT04210986, IND#144317) in addition to an NIH-funded trial examining the effects of senolytic and anti-fibrotic therapies in the setting of knee osteoarthritis with bone marrow concentrate treatment (NCT04815902).

1. Hambright WS, Xiaodong Mu, Yohei Kawakami, John Mitchell, Michael Mullen, Anna-Laura Nelson, Xueqin Gao, Justin Hellwinkel, Andrew Eck, and Johnny Huard. “Senolytic drugs attenuate age-related cartilage and bone degeneration in the Zmpste24-/- progeria mouse model” J. of Osteoporosis. 2021 *Under Review
2. Xiaodong Mu, Chieh Tseng, Hambright WS, Polina Matre, Chih-Yi Lin, Palas Chanda, Wanqun Chen, Jianhua Gu, Sudheer Ravuri, Yan Cui, Ling Zhong, John P. Cooke, Laura J. Niedernhofer, Paul D. Robbins, and Johnny Huard. “RhoA and cytoskeleton stiffness regulate senescence in Hutchinson-Gilford Progeria Syndrome” Aging Cell. 2020. PMC7431831
3. Hambright WS, Robbins Paul D, Huard J, Niedernhofer L. “Murine models of accelerated aging and musculoskeletal disease”. Bone. 2019. PMID30844492
4. Hambright WS & Kawakami Y, Takayama K, Lu A, Cummins J, Tebbets J, Mu X, Matsumoto T, Kuroda R, Kurosaka M, Fu F, Robbins PD, Niedernhofer LJ, Huard J. “Rapamycin rescues age-related changes in muscle-derived stem/progenitor cells from progeroid mice”. Mol Ther Methods Clin Dev. 2019 PMC6610712

Selected Posters and Talks:

1. Hambright WS, Kawakami Y, Mu X, Gao X, Lu A, Eck A, Kirkland J, and Huard J. “Acute fisetin treatment attenuates age-associated bone density loss in the Zmpste24-/- progeria mouse model.” (Podium) ORS General Meeting, Phoenix, AZ, 2020. *NIRA Finalist & ORS travel award recipient
2. Hambright WS, Krishna Sinha, Xiaodong Mu, Andrew Eck, and Johnny Huard. “Expression Profiling of Exosomal miRNAs between C57BL/6 and MRL/MpJ (Super healer) Muscle-Derived Stem/Progenitor Cells.” (Podium) ORS General Meeting, Austin, TX. 2019
3. Hambright WS, Yohei Kawakami, Xiaodong Mu, Xueqin Gao, Aiping Lu, James Kirkland, and Johnny Huard. “Senolytic drugs attenuate bone and articular cartilage degeneration in a progeria mouse model that spontaneously develops age-associated osteoarthritis.” (Podium) ORS General Meeting, Austin, TX. 2019
4. Hambright WS, Mu X, Kawakami Y, Lu A, Cooke J, Huard J. “Transient expression of telomerase (TERT) reduces senescence and improves myogenic differentiation potential in murine and human muscle-derived stem cells (MDSCs).” (Poster) ORS Annual Meeting, New Orleans LA, 2018

Healthy Aging Diagnostics: A key element to our research program is the development of prognostic and diagnostic senescence detection methods using peripheral blood. Using novel flow cytometry based detection methods, we have found senescent cell signatures (biomarkers) in blood serum and blood immune cells that correlate with age and potentially pathology. Our long-term goal is to validate a platform whereby we can track healthy aging and responsiveness to surgical, biological, and senolytic treatments for various orthopaedic conditions.

1. Kloser H, Huard C, Mitchell J, Mullen M, Whitney K, Bahney C, Duke V, O’Hara K, Huard J & Hambright WS. “Detection of human senescent cell populations in peripheral blood using C12FDG”. Methods Journ. 2021 *Under Review

Selected Posters and Talks:

1. William S. Hambright, Charles Huard, John Mitchell, Michael Mullen, Kaitie Whitney, Alyson Fiorentino, Heidi Kloser, and Johnny Huard. “Rapid elimination of senescent PBMCs using the senolytic agent fisetin: Potential Orthobiologic Implications” (Poster Presentation) ORS Annual Meeting 2021.
2. William S. Hambright, Charles Huard, John Mitchell, Kaitie Whitney, Michael Mullen, Alyson Fiorentino, Heidi Kloser, and Johnny Huard. “Senescent CD3+ T-Cells are associated with biomarkers for age related orthopaedic decline” (Poster Presentation) ORS Annual Meeting 2021
3. John Mitchell, Charles Huard, Michael Mullen, William S. Hambright, Kaitie Whitney, Alyson Fiorentino, Sudheer Ravuri, Xueqin Gao, Heidi Kloser, and Johnny Huard. “Methods for the Detection of Senescence Associated Beta Galactosidase in Peripheral Blood Mononuclear Cells from Human Whole Blood using C12FDG and Flow Cytometry” (Poster Presentation) ORS Annual Meeting 2021
4. Michael Mullen, Heidi Kloser, John Mitchell, William S. Hambright, Andrew Eck, Sudheer Ravuri, Johnny Huard. “Exosome Secretion Increases with Culture Expansion and Age in Banked Human Adipose Derived Stem Cells” (Poster Presentation) ORS Annual Meeting 2021

Ferroptosis in Neuronal Cell Death Associated with Cognitive Decline (PhD): As a PhD student at UTHSCSA my research focused on age-related pathologies including cardiovascular disease and age-associated neurodegenerative diseases like Alzheimer’s and Amyotrophic Lateral Sclerosis (ALS). In the Ran laboratory, I studied the protective effects of inducible peroxiredoxin-3 (Prdx3) in astrocytes. We found that mitigating mtROS (H2O2) through Prdx3 overexpression provided protection from ROS induced cell death and reduced NLRP3 inflammasome activation in primary astrocytes. A novel finding regarding inflammatory signaling in astrocytes. In addition, I focused on neurodegenerative mechanisms using contemporary transgenic murine models. We found that neurons in vivo are sensitive to ferroptosis, a newly discovered non-apoptotic but regulated cell death mechanism. Using a novel transgenic mouse system, our lab was the first to discover that motor neurons are quite sensitive to ferroptosis highlighting a potential role in neurodegenerative pathologies of the spinal cord like ALS. In addition, we reported that forebrain neurons, which includes neurons of the cerebral cortex and hippocampus that are essential for learning and memory, are also sensitive to ferroptosis resulting in neurodegeneration and cognitive impairment. We also found that the induction of ferroptosis in mouse models of Alzheimer’s disease could potentially modulate Aβ (plaque) and tau (tangle) deposition, and cognitive decline which are all pathophysiological signatures of Alzheimer’s disease.

1. Chen L, Hambright WS, Na R, Ran Q. “Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis.” J Biol Chem. (PMCID:4653669) 2015.
2. Hambright WS, Fonseca RS, Chen L, Na R, Ran Q. “Ablation of the ferroptosis regulator Gpx4 in forebrain neurons promotes cognitive impairment and neurodegeneration.” Redox Biol. (PMCID:5312549) 2017.

Selected Posters & Talks

1. Hambright WS, Lai Y, Chen L, Ran Q. “Increased NLRP3 Inflammasome expression correlates with Cognitive Decline in animals exposed to a mitochondrial ROS inducer.” (Poster) Nathan Shock Center Conference on Aging. Bandera, TX 2013.
2. Hambright WS, Chen L, Ran Q. “Inducible peroxiredoxin-3 in vivo: A novel tool to mitigate mtH2O2.” (Poster) Nathan Shock Center Conference on Aging. Bandera, TX 2014.
3. Hambright WS. “In vivo models to study neurological disease.” (Talk) Barshop Institute Student Recruitment Weekend. San Antonio, TX 2015.
4. Hambright WS, Chen L, Ran Q. “Overexpression of Prdx3 in astrocytes confers resistance to oxidative stress and suppresses NLRP3 inflammasome priming.” (Poster) Gordon Research Conference: Oxidative stress and Disease. Ventura, CA 2015. *Awarded GRC travel stipend
5. Hambright WS, Chen L, Ran Q. “Ablation of the ferroptosis regulator Gpx4 in forebrain neurons of adult mice results in neurodegeneration and cognitive impairment.” (Talk) Society for Redox Biology and Medicine Annual Meeting, San Francisco, CA 2016. *Awarded SfRBM student travel grant
6. Hambright WS, Chen L, Ran Q. “Ferroptosis: A novel cell death pathway that promotes hippocampal neurodegeneration and cognitive decline.” (Poster) Neurodegenerative Diseases: Biology and Therapeutics Meeting, Cold Springs Harbor Laboratory, NY 2016. *Awarded GSBS student travel grant
7. Hambright WS, Chen L, Ran Q. “Investigation of ferroptosis as a cell death modality in neurodegenerative disease” (Talk) Barshop Institute Biology of Aging Symposium, San Antonio, TX 2017.

Role of Nox4 in Monocyte Dysfunction: The NADPH Oxidase-4 (NOX4) is a ROS-producing enzyme known to regulate monocyte function. While in my PhD program, I collaborated on projects related to the role of NADPH oxidase 4 (Nox4) and monocyte activation and dysfunction related to cardiovascular decline. We found that Nox4 derived H2O2 promoted a more proinflammatory macrophage profile. We also reported that the natural product ursolic acid protected against such monocyte activation.

1. Ullevig SL, Kim HS, Hambright WS, Robles A, Tavakoli S, Asmis R. “Ursolic Acid Protects Monocytes Against Metabolic Stress Induced Priming and Dysfunction by Preventing the Induction of Nox4.” Free Radic. Biol. Med. (PMCID:3909821) 2014.

Transcriptional Divergence in Marine Bacteria (MS): Natural expressional divergence within a bacterial population that can have taxonomic implications in stratified marine environments. Defining a species in prokaryotes is problematic given the genetic fluidity of the organisms. This is especially true in marine bacterium given that environmental barriers are not often present. Using the marine bacterium Shewanella baltica, we studied natural transcriptional divergence among closely related “ecotypes”. With this project, it was concluded that the low-magnitude expressional variance between ecotypes may play a previously unappreciated role in species divergence in a marine ecosystem.

1. Isanapong J, Hambright WS, Willis AG, Boonmee A, Callister SJ, Burnum KE, Paša-Tolić L, Nicora CD, Schmidt TM, Rodrigues JLM. “Development of an ecolophysiological model for Diplosphaera colotermitum, TAV2, a termite hindgut verrucomicrobium.” ISME J. (PMCID:3749508) 2013.
2. Hambright WS, Deng J, Tiedje JM, Brettar I, Rodrigues JLM. “Shewanella baltica ecotypes have a wide transcriptional variation under the same growth conditions.” mSphere. (PMCID:5071532) 2016.

Selected Posters and Talks

1. Hambright WS, Rodrigues JLM. “Understanding eukaryotic ecological specialization through transcriptional variation.” (Talk) American Society for Microbiology Texas Branch Annual Meeting, Tyler, TX. 2009. *Awarded honorable mention
2. Hambright WS, Rodrigues JLM. Rodrigues. “Using Shewanella baltica ecotypes as a model for transcriptional variation at the population level.” (Poster) Ecological Integration     Symposium, College Station, TX 2010.
3. Hambright WS, Rodrigues JLM. Is “Transcriptional Variation an Explanation for the Ecotype Concept? Using a Population of the Marine Bacterium Shewanella baltica.” (Poster) American Society for Microbiology Annual Meeting. San Diego, CA 2010. *Awarded ASM student travel award

Regulation of stomatal immunity in Arabidopsis thaliana: In collaboration with the Melotto lab at UT Arlington, I investigated the regulation of stomatal immunity in Arabidopsis thaliana. Here, it was found that relatively high humidity can compromise stomatal closure in some plants allowing more invasion of infectious bacteria.

1. Panchal S, Chitrakar R, Thompson BK, Obulareddy N, Roy D, Hambright WS, Melotto M. “Regulation of Stomatal Immunity by Air Relative Humidity.” Plant Physiology. (PMCID:5100797) 2016