Development of a stem cell-based therapy for the recovery of skeletal muscle mass following immobilization

Munroe, Michael

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https://hdl.handle.net/2142/101284 Copy

Description

Title

Development of a stem cell-based therapy for the recovery of skeletal muscle mass following immobilization

Author(s)

Munroe, Michael

Issue Date

2018-04-09

Director of Research (if dissertation) or Advisor (if thesis)

Boppart, Marni D.

Doctoral Committee Chair(s)

Boppart, Marni D.

Committee Member(s)

• Dupont-Versteegden, Esther
• Kong, Hyunjoon
• Woods, Jeff

Department of Study

Kinesiology & Community Health

Discipline

Kinesiology

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Disuse Atrophy
• Immobilization
• Skeletal Muscle
• Pericytes
• Transplantation Therapy

Abstract

Skeletal muscle disuse atrophy is a debilitating medical condition that occurs as result of limb immobilization and whole body bed rest. Severe reductions to muscle mass contribute to functional declines, disability, and metabolic comorbidities, such as obesity, Type II diabetes, and cardiovascular disease. Physical rehabilitation is the most commonly prescribed therapy to help recover from disuse atrophy; however, illness and lack of mobility may limit physical activity and full recovery may not be possible, particularly in older adults. Therefore, there is a need to develop novel and more effective rehabilitation strategies. Satellite cells are myogenic progenitor cells that render muscle capable of repair and regeneration, yet the role for these cells in fiber growth and restoration of function following disuse is equivocal. Perivascular stem/stromal cells, including pericytes, reside in close proximity to microvessels, possess myogenic capacity, and secrete various regenerative paracrine factors, making them ideal candidates for stem cell-based therapies. However, minimal information exists regarding their response to periods of disuse or their contribution to muscle recovery upon a return to physical activity. Thus, the purpose of this study was to 1) determine the impact of immobilization and remobilization on pericyte quantity and function, and 2) determine the ability for exogenously administered pericytes to improve recovery following disuse. Utilizing a unilateral hindlimb immobilization model that results in specific atrophy of the tibialis anterior (TA) muscle, relative pericyte content was quantified by multiplex flow cytometry immediately following 14 days of immobilization and following 14 days of remobilization post-disuse. NG2+CD31-CD45- and CD146+CD31-CD45- pericytes were collected using fluorescence-activated cell sorting (FACS) following the remobilization period, and gene expression was analyzed as a readout of functionality. Finally, both pericyte populations were loaded into a biodegradable, low molecular weight RGD-alginate hydrogel and transplanted into atrophied TA muscles prior to remobilization. We observed significant reductions to pericyte quantity with immobilization that was recovered with remobilization. However, pericyte gene expression patterns were not markedly altered at the end of the remobilization period. Interestingly, pericyte transplantation immediately prior to remobilization resulted in significant recovery of myofiber size and muscle capillarization. The data from these experiments suggest that pericytes are reduced following a period of disuse, and importantly, pericyte transplantation improved skeletal muscle recovery when introduced immediately prior to remobilization. These novel findings justify further development of a pericyte-based therapy for the treatment of disuse atrophy.

Graduation Semester

2018-05

Type of Resource

text

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http://hdl.handle.net/2142/101284

Copyright and License Information

Copyright 2018 Michael Munroe

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