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Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Jun 26, 2019; 11(6): 281-296
Published online Jun 26, 2019. doi: 10.4252/wjsc.v11.i6.281
Dysfunctional stem and progenitor cells impair fracture healing with age
Diane R Wagner, Sonali Karnik, Zachary J Gunderson, Jeffery J Nielsen, Alanna Fennimore, Hunter J Promer, Jonathan W Lowery, M Terry Loghmani, Philip S Low, Todd O McKinley, Melissa A Kacena, Matthias Clauss, Jiliang Li
Diane R Wagner, Sonali Karnik, Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
Zachary J Gunderson, Todd O McKinley, Melissa A Kacena, Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States
Jeffery J Nielsen, Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, United States
Alanna Fennimore, M Terry Loghmani, Department of Physical Therapy, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
Hunter J Promer, Jonathan W Lowery, Division of Biomedical Science, Marian University College of Osteopathic Medicine, Indianapolis, IN 46222, United States
Philip S Low, Department of Chemistry, Purdue University, West Lafayette, IN 47907 United States
Melissa A Kacena, Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, United States
Matthias Clauss, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
Jiliang Li, Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
Author contributions: All authors contributed to this paper with conception and design of the study, literature review and analysis, drafting and critical revision and editing, and approval of the final version.
Supported by in part of the following grants: Indiana University Collaborative Research Grant; Indiana Clinical and Translational Sciences Institute, No. NIH UL1TR001108, No. NIH R01 AR069657, No. NIH R01 AR060863 and No. NIH R01 AG060621. This material is also the result of work supported with resources and the use of facilities at the Richard L. Roudebush VA Medical Center, Indianapolis, IN, VA Merit, No. BX003751; the contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.
Conflict-of-interest statement: No potential conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Diane R Wagner, PhD, Associate Professor, Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, 723 W. Michigan St. SL 260, Indianapolis, IN 46220, United States. wagnerdi@iupui.edu
Telephone: +1-317-2748958 Fax: +1-317-2744567
Received: March 21, 2019
Peer-review started: March 22, 2019
First decision: April 11, 2019
Revised: April 26, 2019
Accepted: June 12, 2019
Article in press: June 12, 2019
Published online: June 26, 2019
Abstract

Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature; mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells. MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs. Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. Some suggested directions for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics. Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging; a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.

Keywords: Fracture healing, Aging, Bone, Angiogenesis, Mesenchymal stem cells, Endothelial progenitor cells

Core tip: Bone fractures in the elderly are a significant issue, due to the prevalence of the problem, the difficulty of treatment, and the severe consequences of the extended healing period. The delay in fracture healing with advanced age has been attributed to both the decreased number and function of mesenchymal stem cells that regenerate the bone and the inferior performance of endothelial progenitor cells that direct angiogenesis. Some suggested avenues for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics.