A New Stem Cell Immune Rejection Discovery Shows Promise for Treating Retinal Disease

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Cell Stem Cell

A joint China-United States research team has discovered that a class of stem cells derived from an individual's own cells were not rejected by the immune system when they were turned into retinal pigment epithelium cells destined for the eye.

This important discovery provides a boost for the development of human stem cell therapies to treat age-related macular degeneration (AMD). Although this research has been conducted only with laboratory mice, this concept shows great promise for developing and identifying human stem cell treatments for a variety of retinal disorders.

For more information about ongoing and projected stem cell clinical trials for AMD, you can read Adult Stem Cells for Dry AMD: Emerging Future Research from the National Eye Institute; Positive Stem Cell Clinical Trial Results for Stargardt Disease and Dry Macular Degeneration; and Newly Discovered Corneal Stem Cells Could Be a Potential Source for Treatment of Retinal Disease on the VisionAware blog.

The Stem Cell Research

The research, entitled Humanized Mice Reveal Differential Immunogenicity of Cells Derived from Autologous Induced Pluripotent Stem Cells (explained below), has been published online ahead-of-print in the August 20, 2015 edition of Cell Stem Cell.

The authors are Tongbiao Zhao, Zhen-ning Zhang, Peter D. Westenskow; Dilyana Todorova, Zheng Hu, Tongxiang Lin, Zhili Rong, Jinchul Kim, Jingjin He, Meiyan Wang, Dennis O. Clegg, Yong-guang Yang, Kun Zhang, Martin Friedlander, and Yang Xu, who represent the following institutions: the University of California, San Diego; the Chinese Academy of Sciences, Beijing; The Scripps Research Institute, La Jolla, CA; First Hospital of Jilin University, Jilin, China; Guangzhou University of Traditional Chinese Medicine, China; Southern Medical University, Guangzhou, China; the University of California, Santa Barbara; and Columbia University Medical Center, New York.

Cell Stem Cell is affiliated with the International Society for Stem Cell Research and covers the entire spectrum of stem cell biology. The journal reports on topics that are relevant to stem cell research, including basic biological advances and ethical, policy, and funding issues.

Some Relevant Stem Cell Terminology

Here is a brief explanation of the key stem cell concepts and terms used by the researchers:

  • Pluripotent: A stem cell that has the power to develop into any type of bodily cell or tissue ("pluri" = many; "potent" = having power).
  • Induced pluripotent stem cell (iPSC): A type of pluripotent stem cell that can be generated directly from adult cells.
  • Autologous: Involving one individual as both donor and recipient
  • Retinal pigment epithelium (RPE) cells: The deepest cells of the retina. The RPE helps to maintain the health of the retinal photoreceptor cells, called rods and cones. These photoreceptor cells are triggered by light to set off a series of electrical and chemical reactions that helps brain to interpret what the eye sees. The degeneration of the RPE cells also leads to the death of the rods and cones and, ultimately, vision.
  • Immunogenic: Causing, or capable of producing, an immune response.
  • Murine: Related to mice, or using a mouse model in research.

About the Stem Cell/Immune Response Research

Excerpted from Study provides hope for some human stem cell therapies at Medical Xpress:

An international team of scientists … has discovered that an important class of stem cells known as human "induced pluripotent stem cells," or iPSCs, which are derived from an individual's own cells, can be differentiated into various types of functional cells with different fates of immune rejection.

The scientists also found that these cells may not be rejected by the immune system if iPSCs are turned into retinal pigment epithelium cells destined for the eye. Their discovery provides hope for the development of human stem cell therapies to treat macular degeneration.

The research effort was headed by Yang Xu, a biology professor at UC San Diego who discovered with colleagues in 2011 that even though iPSCs are derived from an individual's own cells, the abnormal gene expression can cause the immune system to reject certain cells derived from iPSCs.

That could have been a major impediment to the safe use of iPSCs, which are regarded as particularly attractive candidates for stem cell therapies because they can be differentiated into a wide variety of cell types, are not derived from embryonic tissue, and are not subject to restrictions that limit the use of human embryonic stem cells.

Funded by a $5.12 million grant from the California Institute for Regenerative Medicine, [study author] Xu and his colleagues earlier developed "humanized" laboratory mice with a functional human immune system capable of mounting a vigorous immune rejection of foreign cells derived human embryonic stem cells. "Human and mouse immune systems are quite different," explained Xu, "so we developed a humanized laboratory mouse that carries a functional human immune system. This provides a unique opportunity to evaluate the human immune responses to stem cells."

In their experiments, the researchers developed a variety of cell types from human iPSCs, then tested the immune responses in humanized mice with the immune system of the same individual. They discovered that smooth muscle cells were highly "immunogenic," or strongly rejected by the immune systems of the humanized mice, while retinal pigment epithelial cells were tolerated by the immune system, even when transplanted in parts of the body that provide the environment for robust immune rejection.

"Immune rejection is a major challenge for stem cell therapy," Xu said. "Our finding of the lack of immune rejection of human iPSC-derived retinal pigment epithelium cells supports the feasibility of using these cells for treating macular degeneration. However, the inflammatory environment associated with macular degeneration could be an additional hurdle to be overcome for the stem cell therapy to be successful."

More about Induced Pluripotent Stem Cells

From Wikipedia:

Induced pluripotent stem cells (also known as iPS cells or iPSCs) are a type of pluripotent stem cell that can be generated directly from adult cells. Pluripotent stem cells hold great promise in the field of regenerative medicine. Because they can propagate indefinitely, as well as give rise to every other cell type in the body (such as neurons, heart, pancreatic, and liver cells), they represent a single source of cells that could be used to replace those lost to damage or disease.

The most well-known type of pluripotent stem cell is the embryonic stem cell. However, since the generation of embryonic stem cells involves destruction (or at least manipulation) of the pre-implantation stage embryo, there has been much controversy surrounding their use. Further, because embryonic stem cells can only be derived from embryos, it has so far not been feasible to create patient-matched embryonic stem cell lines.

Since iPSCs can be derived directly from adult tissues, they not only bypass the need for embryos, but can be made in a patient-matched manner, which means that each individual could have their own pluripotent stem cell line. These unlimited supplies of autologous cells could be used to generate transplants without the risk of immune rejection.

[Please note: Although adult/iPSC research does not use human embryos and thus sidesteps the ethical issues surrounding their use, there are still significant risks associated with the use of autologous stem cells, including teratomas, or tumor formation.]

Age-Related Macular Degeneration

NEI image of how someone with macular degeneration sees: overall blurriness with a blind spot in the center

What a person with AMD sees

Age-related macular degeneration (AMD) is gradual, progressive, painless deterioration of the macula, the small sensitive area in the center of the retina that provides clear central vision. The fovea is located in the center of the macula and provides the sharpest detail vision.

AMD is the leading cause of vision loss for people aged 60 and older in the United States. According to the American Academy of Ophthalmology, 10-15 million individuals have AMD; approximately 10% of people who are affected have the "wet" type of AMD. For more information about vision loss from AMD, see How Does AMD Affect Vision? by Lylas G. Mogk, M.D.

Wet Macular Degeneration (AMD)

In wet, or exudative, macular degeneration (AMD), the choroid (a part of the eye containing blood vessels that nourish the retina) begins to sprout abnormal new blood vessels that develop into a cluster under the macula, called choroidal neovascularization (neo = new; vascular = blood vessels).

The macula is the part of the retina that provides the clearest central vision. Because these new blood vessels are abnormal, they tend to break, bleed, and leak fluid under the macula, causing it to lift up and pull away from its base. This damages the fragile photoreceptor cells, which sense and receive light, resulting in a rapid and severe loss of central vision.

Dry Macular Degeneration

The dry (also called "atrophic") type of AMD affects approximately 80-90% of individuals with AMD. Its cause is unknown, it tends to progress more slowly than the wet type, and there is not – as of yet – an approved treatment or cure. "Atrophy" refers to the degeneration of cells in a portion of the body; in this case, the cell degeneration occurs in the retina.

In dry age-related macular degeneration, small white or yellowish deposits, called drusen, form on the retina, in the macula, causing it to deteriorate or degenerate over time. These small yellow deposits beneath the retina are a buildup of waste materials, composed of cholesterol, protein, and fats. Typically, when drusen first form, they do not cause vision loss. However, they are a risk factor for progressing to vision loss.

More about the Research from Cell Stem Cell

Excerpted from the article Summary:

The breakthrough of induced pluripotent stem cell (iPSC) technology has raised the possibility that patient-specific iPSCs may become a renewable source of autologous cells for cell therapy without the concern of immune rejection. However, the immunogenicity of autologous human iPSC (hiPSC)-derived cells is not well understood.

Using a humanized mouse model (denoted Hu-mice) reconstituted with a functional human immune system, we demonstrate that most teratomas formed by autologous integration-free hiPSCs exhibit local infiltration of antigen-specific T cells and associated tissue necrosis, indicating immune rejection of certain hiPSC-derived cells.

In this context, autologous hiPSC-derived smooth muscle cells (SMCs) appear to be highly immunogenic, while autologous hiPSC-derived retinal pigment epithelial (RPE) cells are immune tolerated even in non-ocular locations.

This differential immunogenicity is due in part to abnormal expression of immunogenic antigens in hiPSC-derived SMCs, but not in hiPSC-derived RPEs. These findings support the feasibility of developing hiPSC-derived RPEs for treating macular degeneration.

Stem Cell Research from VisionAware


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