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Induced Pluripotent Stem Cell-derived Mesenchymal Progenitor Cells: Promotion of Neuritogenesis and Axon Elongation through Neurotrophin and Cytokine Production

Brick, Rachel (2017) Induced Pluripotent Stem Cell-derived Mesenchymal Progenitor Cells: Promotion of Neuritogenesis and Axon Elongation through Neurotrophin and Cytokine Production. Doctoral Dissertation, University of Pittsburgh.

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Abstract

Adult bone marrow derived, multipotent mesenchymal stem cells (MSCs) have been shown to exhibit support nerve regeneration by secreting neurotrophic factors typically produced by Schwann cells. However, MSCs have limited expansion capacity, and therefore have limited lifespan and use.

Induced pluripotent stem cells (iPSCs) can potentially overcome this drawback—iPSCs are adult cells reprogrammed with pluripotency factors to become like embryonic stem cells. Thus, MSCs may be taken from a patient and reprogrammed into iPSCs, such that their expansion capacity is virtually unlimited. After expansion, the iPSCs can be differentiated once again into mesenchymally-derived induced mesenchymal progenitor cells (MiMPCs). This technology has the potential to yield an almost unlimited supply of MSC-like cells.

We report here that MiMPCs can be induced to produce neurotrophic factors (NTFs) such as brain-derived neurotrophic factor (BDNF) at levels comparable to those produced by MSCs. NTF production further increases when MiMPCs are induced in a simulated inflammatory environment. MiMPCs are also capable of producing multiple other factors and cytokines that have been shown to enhance nerve regeneration, including osteonectin and IL-6.

Our results show that treatment with conditioned medium derived from MiMPCs and MSCs resulted in enhanced neuritogenesis and extension lengths of cultures of chick embryonic dorsal root ganglia (DRG). MiMPC/DRG co-cultures grown on 2-dimensional electrospun nanofibrous biomaterial scaffolds are also comparable morphologically and physiologically to MSC/DRG scaffold co-cultures. In these cultures, neurite length is significantly decreased with the introduction of a Jak/STAT inhibitor, suggesting that secreted cytokines from the IL-6 family are required for neurite extensions. Complexity of these neurite extensions decreases, but is not abolished, when Trk-receptor inhibitors are applied, suggesting the involvement of other non-traditional neurotrophic factors in the MiMPC secretome in the enhancement of neuritogenesis.

Taken together, these results strongly suggest that MiMPCs may be a suitable clinical replacement for MSCs in nerve regeneration cell therapeutics. Future assessment of this therapeutic potential will include testing the efficacy of an MiMPC-seeded nerve conduit to repair peripheral nerve injury in an experimental animal model, such as the rat sciatic nerve transection model.


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Details

Item Type: University of Pittsburgh ETD
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Brick, Rachelrbrick135@gmail.comrmb135
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorTuan, Rockyrst13@pitt.edu
Committee ChairChu, Charleenctc4@pitt.edu
Committee MemberCui, Tracyxic11@pitt.edu
Committee MemberSoto-Gutierrez, Alejandroals208@pitt.edu
Committee MemberHuard, JohnnyJohnny.Huard@uth.tmc.edu
Date: 14 July 2017
Date Type: Publication
Defense Date: 12 June 2017
Approval Date: 14 July 2017
Submission Date: 13 July 2017
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 154
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: stem cells, nerve injury, regenerative medicine, nerve regeneration
Date Deposited: 14 Jul 2017 17:01
Last Modified: 14 Jul 2017 17:01
URI: http://d-scholarship.pitt.edu/id/eprint/32748

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