Publications by authors named "Lea Ann Thompson"

5 Publications

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Therapeutic application of Sertoli cells for treatment of various diseases.

Semin Cell Dev Biol 2021 Apr 25. Epub 2021 Apr 25.

Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Medical Education, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA. Electronic address:

Sertoli cells (SCs) are immune privileged cells found in the testis that function to immunologically protect maturing germ cells from immune destruction. This immune protection is due to the blood-testis-barrier, which prevents infiltration of cytotoxic immune cells and antibodies, and SC production of immunomodulatory factors, that favor a tolerogenic environment. The ability of SCs to create an immune privileged environment has led to the exploration of their potential use in the treatment of various diseases. SCs have been utilized to create a tolerogenic ectopic microenvironment, to protect co-grafted cells, and to deliver therapeutic proteins through gene therapy. To date, numerous studies have reported the potential use of SCs for the treatment of diabetes, neurodegenerative disorders, and restoration of spermatogenesis. Additionally, SCs have been investigated as a delivery vehicle for therapeutic products to treat other diseases like Laron syndrome, muscular dystrophy, and infections. This review will provide an overview of these therapeutic applications.
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http://dx.doi.org/10.1016/j.semcdb.2021.04.007DOI Listing
April 2021

Neonatal Pig Sertoli Cells Survive Xenotransplantation by Creating an Immune Modulatory Environment Involving CD4 and CD8 Regulatory T Cells.

Cell Transplant 2020 Jan-Dec;29:963689720947102

Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA.

The acute cell-mediated immune response presents a significant barrier to xenotransplantation. Immune-privileged Sertoli cells (SC) can prolong the survival of co-transplanted cells including xenogeneic islets, hepatocytes, and neurons by protecting them from immune rejection. Additionally, SC survive as allo- and xenografts without the use of any immunosuppressive drugs suggesting elucidating the survival mechanism(s) of SC could be used to improve survival of xenografts. In this study, the survival and immune response generated toward neonatal pig SC (NPSC) or neonatal pig islets (NPI), nonimmune-privileged controls, was compared after xenotransplantation into naïve Lewis rats without immune suppression. The NPSC survived throughout the study, while NPI were rejected within 9 days. Analysis of the grafts revealed that macrophages and T cells were the main immune cells infiltrating the NPSC and NPI grafts. Further characterization of the T cells within the grafts indicated that the NPSC grafts contained significantly more cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8) regulatory T cells (Tregs) at early time points than the NPI grafts. Additionally, the presence of increased amounts of interleukin 10 (IL-10) and transforming growth factor (TGF) β and decreased levels of tumor necrosis factor (TNF) α and apoptosis in the NPSC grafts compared to NPI grafts suggests the presence of regulatory immune cells in the NPSC grafts. The NPSC expressed several immunoregulatory factors such as TGFβ, thrombospondin-1 (THBS1), indoleamine-pyrrole 2,3-dioxygenase, and galectin-1, which could promote the recruitment of these regulatory immune cells to the NPSC grafts. In contrast, NPI grafts had fewer Tregs and increased apoptosis and inflammation (increased TNFα, decreased IL-10 and TGFβ) suggestive of cytotoxic immune cells that contribute to their early rejection. Collectively, our data suggest that a regulatory graft environment with regulatory immune cells including CD4 and CD8 Tregs in NPSC grafts could be attributed to the prolonged survival of the NPSC xenografts.
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http://dx.doi.org/10.1177/0963689720947102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564626PMC
July 2021

Sertoli Cells Engineered to Express Insulin to Lower Blood Glucose in Diabetic Mice.

DNA Cell Biol 2018 Aug 21;37(8):680-690. Epub 2018 Jun 21.

Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center , Lubbock, Texas.

Long-term survival of allo- and xenotransplanted immune-privileged Sertoli cells (SCs) is well documented suggesting that SCs can be used to deliver foreign proteins for cell-based gene therapy. The aim of this study was to use a lentivirus carrying proinsulin cDNA to achieve stable expression and lowering of blood glucose levels (BGLs). A SC line transduced with the lentivirus (MSC-LV-mI) maintained stable insulin expression in vitro. These MSC-LV-mI cells were transplanted and grafts were analyzed for cell survival, continued proinsulin mRNA, and insulin protein expression. All grafts contained MSC-LV-mI cells that expressed proinsulin mRNA and insulin protein. Transplantation of MSC-LV-mI cells into diabetic mice significantly lowered BGLs for 4 days after transplantation. Interestingly, in three transplanted SCID mice and one transplanted BALB/c mouse, the BGLs again significantly lowered by day 50 and 70, respectively. This is the first time SC transduced with a lentiviral vector was able to stably express insulin and lower BGLs. In conclusion, a SC line can be modified to stably express therapeutic proteins (e.g., insulin), thus taking us one step further in the use of SCs as an immune-privileged vehicle for cell-based gene therapy.
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http://dx.doi.org/10.1089/dna.2017.3937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6080125PMC
August 2018

Sustained expression of insulin by a genetically engineered sertoli cell line after allotransplantation in diabetic BALB/c mice.

Biol Reprod 2014 May 2;90(5):109. Epub 2014 Apr 2.

Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas

Immune-privileged Sertoli cells (SCs) exhibit long-term survival after allotransplantation or xenotransplantation, suggesting they can be used as a vehicle for cell-based gene therapy. Previously, we demonstrated that SCs engineered to secrete insulin by using an adenoviral vector normalized blood glucose levels in diabetic mice. However, the expression of insulin was transient, and the use of immunocompromised mice did not address the question of whether SCs can stably express insulin in immunocompetent animals. Thus, the objective of the current study was to use a lentiviral vector to achieve stable expression of insulin in SCs and test the ability of these cells to survive after allotransplantation. A mouse SC line transduced with a recombinant lentiviral vector containing furin-modified human proinsulin cDNA (MSC-EhI-Zs) maintained stable insulin expression in vitro. Allotransplantation of MSC-EhI-Zs cells into diabetic BALB/c mice demonstrated 88% and 75% graft survival rates at 20 and 50 days post-transplantation, respectively. Transplanted MSC-EhI-Zs cells continued to produce insulin mRNA throughout the study (i.e., 50 days); however, insulin protein was detected only in patches of cells within the grafts. Consistent with low insulin protein detection, there was no significant change in blood glucose levels in the transplant recipients. Nevertheless, MSC-EhI-Zs cells isolated from the grafts continued to express insulin protein in culture. Collectively, this demonstrates that MSC-EhI-Zs cells stably expressed insulin and survived allotransplantation without immunosuppression. This further strengthens the use of SCs as targets for cell-based gene therapy for the treatment of numerous chronic diseases, especially those that require basal protein expression.
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http://dx.doi.org/10.1095/biolreprod.113.115600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076370PMC
May 2014

Sertoli cells--immunological sentinels of spermatogenesis.

Semin Cell Dev Biol 2014 Jun 3;30:36-44. Epub 2014 Mar 3.

Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, United States. Electronic address:

Testicular germ cells, which appear after the establishment of central tolerance, express novel cell surface and intracellular proteins that can be recognized as 'foreign antigens' by the host's immune system. However, normally these germ cells do not evoke an auto-reactive immune response. The focus of this manuscript is to review the evidence that the blood-testis-barrier (BTB)/Sertoli cell (SC) barrier along with the SCs ability to modulate the immune response is vital for protecting auto-antigenic germ cells. In normal testis, the BTB/SC barrier protects the majority of the auto-antigenic germ cells by limiting access by the immune system and sequestering these 'new antigens'. SCs also modulate testis immune cells (induce regulatory immune cells) by expressing several immunoregulatory factors, thereby creating a local tolerogenic environment optimal for survival of nonsequesetred auto-antigenic germ cells. Collectively, the fortress created by the BTB/SC barrier along with modulation of the immune response is pivotal for completion of spermatogenesis and species survival.
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http://dx.doi.org/10.1016/j.semcdb.2014.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4043859PMC
June 2014