Cheng, Haizi
(2019)
THE ROLE OF BONE MORPHOGENETIC PROTEIN IN REGULATING CELL CYCLE OF AGED MUSCLE-DERIVED STEM CELLS OSTEOGENIC POTENTIAL IN VITRO AND BONE REGENERATION IN VIVO.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Bone morphogenetic protein 4 (BMP4) promotes the osteogenic potential & the bone regenerative potential of muscle-derived stem cells (MDSCs). However, the osteogenic potential of MDSCs is progressively lost during the aging process. In fact, we show here that aged murine MDSCs (MDSCs) exhibit reduced proliferation and multi-lineage differentiation potential with or without BMP4 stimulation in vitro, when compared to young murine MDSCs. We also showed that aged MDSCs retrovirally transduced to express BMP4 can regenerate bone in a critical-sized skull defect in 6-week-old CD-1 nude mice, but the bone regenerative potential is inferior to young BMP4 expressing MDSCs. Interestingly both young and aged MDSCs can regenerate more bone when BMP4 is over-expressed with the retrovirus-BMP4. BMP4-transduced aged MDSCs over-expressing BMP4, showed a significant enhancement of osteogenic and bone regenerative potential when compared to aged MDSCs expressing low levels of BMP4 after a single transduction. It has been reported that BMP promotes the self-renewal of both embryonic and somatic stem cells and that BMP signaling activity significantly decreases with age, thus we posit that BMP induction may improve the function of MDSCs. We hypothesized that BMP4 might exert beneficial effects through modulation of p16 and p18 expression in transduced MDSCs since the cyclin-dependent kinase inhibitors p16INK4A (p16) and p18INK4C (p18) cause early G1-phase cell cycle blockade. Our results indicate that p18 is temporarily upregulated while p16 is downregulated after BMP4 over-expression indicating a potential mechanism by which BMP4 can offset the effect of aging on the osteogenic potential and the bone regenerative potential of aged MDSCs. These results taken together suggest that BMP4 regulates the cell cycle of aged MDSCs and consequently promotes their osteogenic potential in vitro and in vivo.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
23 August 2019 |
| Date Type: |
Publication |
| Defense Date: |
22 July 2019 |
| Approval Date: |
23 August 2019 |
| Submission Date: |
20 August 2019 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
150 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
BMP4, mMDSCs osteogenesis, p16 and p18 |
| Date Deposited: |
23 Aug 2019 12:00 |
| Last Modified: |
23 Aug 2019 12:00 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/37396 |
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