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Mechanisms of Human CD34+ Stem Cell-Mediated Regulation of Osteoporosis in a Preclinical Model

Aggarwal, Reeva
http://rave.ohiolink.edu/etdc/view?acc_num=osu1354637444

Abstract Details

2012, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
Osteoporosis is a systemic metabolic bone disorder characterized by low mineral density and micro architectural deterioration of skeleton. Osteoporosis or “porous bone” disease can progress asymptomatically until bones fracture. It is a major cause of morbidity and health care burden worldwide. Lack of physical activity, hormonal disturbances, age, gender, heredity and nutritional deficiency are some the factors implicated in causing the disease. Physiologically, bone is a dynamic organ that constantly undergoes remodeling. Bone consists of dense organic and inorganic components. At cellular level, balance/coupling between the activities of bone forming cells (osteoblasts) and bone resorbing cells (osteoclasts) maintains bone homeostasis. Increased bone loss due to increased osteoclast and decreased osteoblast activities is considered as an underlying cause of osteoporosis. Several therapies such as hormone replacement therapy in women, administration of anti-resorptives (bisphosphonates), implantation of osteoinductive device combined with change in lifestyle offers only temporary augmentation of bone mineral density with side effects. Consequently, the potential of stem cell based therapies is currently being considered. Adult stem cells expressing CD133/CD34 surface marker are multipotent cells that can be isolated from human umbilical cord blood and differentiated into many cell lineages by changing the molecular cues in their microenvironment. However, their limited numbers from a single unit restricts their experimental use. Our lab developed a nanofiber-based expansion technology to obtain adequate numbers of CD34+ cells isolated for experimental use and potential therapeutic applications. Herein, we show that nanofiber-expanded CD34+ cells could be differentiated into osteoblastic lineage, in vitro. Systemically delivered CD34+ cells home to the bone marrow and significantly improve bone deposition, BMD and bone micro-architecture in osteoporotic aged nonobese diabetic severe combined immunodeficient (NOD/SCID) mice. The elevated levels of osteocalcin, IL-10, GM-CSF, and decreased levels of MCP-1 in serum parallel the improvements in bone micro-architecture. Furthermore, CD34+ cells improved osteoblast activity and concurrently impaired osteoclast differentiation, maturation, and functionality. Mechanistically, CD34+ cells offer osteoprotection via the upregulation of osteoblastic factors such as Runt-related transcription factor 2 (Runx2) and its downstream effectors such as collagen type I alpha1 and osteocalcin. Consistent with our in vivo observations of impaired osteoclastic activities after CD34+ stem cell therapy, CD34+ cells have the ability to regulate nuclear translocation of osteoclastogenic differentiation factor called nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), and thus negatively regulating its downstream transcriptional activity, and osteoclastogenesis. Taken together, these findings demonstrate a novel approach of utilizing nanofiber-expanded CD34+ cells as a therapeutic application for the treatment of osteoporosis in a preclinical model.
Hiranmoy Das, Dr./Ph.D. (Advisor)
Periannan Kuppusamy, Dr./Ph.D. (Committee Member)
Sudha Agarwal, Dr./Ph.D. (Committee Member)
Nancy Lill, Dr./Ph.D. (Committee Member)
126 p.
Biomedical Research
"Umbilical Cord; CD34+ cells; Osteoblast; Osteoclast"

Recommended Citations

Citations

  • Aggarwal, R. (2012). Mechanisms of Human CD34+ Stem Cell-Mediated Regulation of Osteoporosis in a Preclinical Model [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1354637444

    APA Style (7th edition)

  • Aggarwal, Reeva. Mechanisms of Human CD34+ Stem Cell-Mediated Regulation of Osteoporosis in a Preclinical Model. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1354637444.

    MLA Style (8th edition)

  • Aggarwal, Reeva. "Mechanisms of Human CD34+ Stem Cell-Mediated Regulation of Osteoporosis in a Preclinical Model." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1354637444

    Chicago Manual of Style (17th edition)

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© 2012, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.
Release 3.2.12