Mesenchymal stem cells (MSCs) are currently being evaluated in over 180 open clinical trials for the treatment of a variety of human diseases. Despite the growing use of MSCs in clinical therapy, many MSC-based clinical trials have failed to meet their primary endpoint of efficacy and patient outcomes have been poorly predicted based on cell potency studies conducted in vitro or in experimental animal models. Indeed, lack of knowledge regarding the functional complexity of MSC populations, pathways that specify cellular behaviors that contribute to cell potency, and species differences in these pathways represent a major impediment toward developing optimized and predictable clinical therapies. To overcome these limitations, this proposal will compare and contrast species differences in the basic biology of rodent and human MSCs, determine how different biological functions that affect cell potency are specified within populations, and demonstrate a functional link between pathways that regulate basic cell biology and non-progenitor functions. To enhance the value of pre-clinical animal models, this laboratory will also create a repository of MSCs from different inbred, transgenic, and knockout strains of mice and supply these cells to the greater scientific community. Methods used to produce cells yield non-immortalized, non-clonal populations that recapitulate the functional complexity and behavior of human MSCs. Consequently, their use provides a means to standardize biological and translational studies across laboratories and between different experimental animal models, thereby augmenting the value, of rodent models for predicting cellular behaviors in the clinical arena.

Public Health Relevance

By contributing new knowledge regarding species differences in MSC biology and developing and distributing rodent MSCs of the highest quality, these studies will improve human health by providing essential pre-clinical knowledge that will inform ongoing and future MSC-based clinical therapies, thereby improving efficacy.

Agency
National Institute of Health (NIH)
Institute
Office of The Director, National Institutes of Health (OD)
Type
Resource-Related Research Projects (R24)
Project #
5R24OD018254-02
Application #
8848903
Study Section
Special Emphasis Panel (ZOD1)
Program Officer
Mirochnitchenko, Oleg
Project Start
2014-05-15
Project End
2018-02-28
Budget Start
2015-03-01
Budget End
2016-02-29
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458
Boregowda, Siddaraju V; Krishnappa, Veena; Strivelli, Jacqueline et al. (2018) Basal p53 expression is indispensable for mesenchymal stem cell integrity. Cell Death Differ 25:677-690
Boregowda, Siddaraju V; Ghoshal, Sarbani; Booker, Cori N et al. (2017) IP6K1 Reduces Mesenchymal Stem/Stromal Cell Fitness and Potentiates High Fat Diet-Induced Skeletal Involution. Stem Cells 35:1973-1983
Boregowda, Siddaraju V; Krishnappa, Veena; Phinney, Donald G (2016) Isolation of Mouse Bone Marrow Mesenchymal Stem Cells. Methods Mol Biol 1416:205-23
Boregowda, Siddaraju V; Krishnappa, Veena; Haga, Christopher L et al. (2016) A Clinical Indications Prediction Scale Based on TWIST1 for Human Mesenchymal Stem Cells. EBioMedicine 4:62-73
Galipeau, Jacques; Krampera, Mauro; Barrett, John et al. (2016) International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy 18:151-9
Yang, Rui; Piperdi, Sajida; Zhang, Yue et al. (2016) Transcriptional Profiling Identifies the Signaling Axes of IGF and Transforming Growth Factor-b as Involved in the Pathogenesis of Osteosarcoma. Clin Orthop Relat Res 474:178-89
Boregowda, Siddaraju V; Phinney, Donald G (2016) Quantifiable Metrics for Predicting MSC Therapeutic Efficacy. J Stem Cell Res Ther 6:
Phinney, Donald G; Di Giuseppe, Michelangelo; Njah, Joel et al. (2015) Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun 6:8472
Marciano, David P; Kuruvilla, Dana S; Boregowda, Siddaraju V et al. (2015) Pharmacological repression of PPAR? promotes osteogenesis. Nat Commun 6:7443