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This figure from 1 explains how key cause of blindness in several eye-related conditions such as AMD (Age-related Macular Degeneration) and juvenile macular dystrophies is dysfunction and/or damage to the RPE (Retinal Pigment Epithelium).

Thus, ability to generate RPE in culture has been the key focus of recent research in vision science. Scientists have tested a variety of cells, particularly stem cells, for their capacity to differentiate into RPE. These are then transplanted into patients with damaged retina.

  • In humans, the RPE itself contains a few stem cells that can differentiate into new RPE cells as well as into cells with a neuronal phenotype (2). However, the retina is not a practical source material for patients seeking Rx since they obviously have damaged retina to start with.
  • OTOH, in vitro fertilization typically leads to excess blastocysts. Over the years, blastocyst-derived embryonic stem cells (ESC) have served as a much more practical starting material. First isolated and cultured in 1998 (3), human ESC (hESC) can be coaxed into differentiating into a fully organized retina, including the RPE (4).
  • Then there are ADSC (Adipose derived stem cells), BMSC (Bone-marrow-derived mesenchymal stem cells), DPSC (Dental Pulp-derved stem cells), iPSC (induced Pluripotent stem cells), NSC (Neural stem cells), all of which can also be differentiated into RPE cells.
  • To better understand their similarities and differences, it may be useful at this stage to consider the types of stem cells being used to derive RPE (see Table below from 5).

A brief overview of the process from tissue/blastocyst to stem cell differentiation to RPE (see figures below from 5 and 6).

And finally, key events in the scientific journey from basic research to ongoing clinical trials to reverse AMD and other types of vision loss using stem cell-derived RPE (see figure below from 1).

Minimizing Immune Responses Against Stem Cell-derived Retinal Transplants a Critical Consideration

The safest source of stem cell-derived RPE is autologous, i.e., derived from the person’s own body, be it from their bone marrow or fat, dental pulp, etc. Since autologous cell source isn’t always available or practical, genetically mismatched, i.e., allogeneic tissues are often used. Problem is allogeneic tissues can drive immune responses against themselves, especially if capillary barrier is breached during transplant, a process that can’t always be perfectly controlled. If such responses are damaging, i.e., immuno-pathological, the treated eye can go blind, defeating the purpose of the Rx. While a variety of sources yield stem cells that can be coaxed to differentiate into RPE, when allogeneic starting material is used, preventing damaging immune responses remains a technical challenge. From this standpoint, ESC are allogeneic to start with while iPSC and MDSC could be allogeneic if derived from donors and not from patients themselves.

A priori, the vitreous and aqueous chambers of the eye are tissues that support rather unique types of immune responses, responses that tend to be much less tissue-damaging. Long ago, this propensity was erroneously labeled ‘immune privileged‘, implying these sites prevented immune responses. Of course, this is absolutely incorrect but unfortunately, the terminology drags on in usage. If interested, any review, like this one (7), by the late J. Wayne Streilein, who discovered this phenomenon, would be a good starting point to learn about this fascinating sub-field.

In early stage human clinical trials, ESC-derived RPE cells transplanted into the retina were found to be safe, i.e., this Rx was safe (8, 9). Since the ESC are genetically different from the patients, i.e., allogeneic, anti-graft immunity could possibly be triggered leading to rejection of the ESC-derived RPE transplants. Thus, patients in these trials were simultaneously treated with immunosuppressive drugs throughout to minimize transplant rejection, a major disadvantage of this approach.

OTOH, studies showed that allogeneic BMSCs tend to inhibit or prevent damaging immunity (10, 11). This accelerated their clinical translation. Currently, there are several ongoing clinical trials testing safety and efficacy of a variety of stem cell-derived RPE to treat AMD, Glaucoma, Diabetic Retinopathy, and other eye diseases (See Tables below from 6 and 12).

RPE derived from different source material aren’t identical

Are RPE derived from different cell types the same? One study compared gene expression profiles of RPE derived from ESC and iPSC to that of human fetal RPE (13). Those derived from ESC overlapped more with those of the fetal human RPE compared to those from iPSC, suggesting ESC-derived but not iPSC-derived RPE recapitulate retina tissue expression better. This critical finding suggests researchers in the field should choose cell source for stem cell-derived RPE judiciously since it’s possible that

  • Some stem cell-derived RPEs may recapitulate vision function better compared to others.
  • Some may trigger anti-graft immune responses more easily than others.

Given concerns of pathologic immune responses as well as cancer-inducing potential of stem cell-derived RPE transplants, a variety of precautions are necessary to ensure purity and safety of these complex biologic therapeutics. See Table below  from (5) for a summary of such precautions, their advantages as well as their limitations.

Bibliography

  1. Jha, Balendu Shekhar, and Kapil Bharti. “Regenerating Retinal Pigment Epithelial Cells to Cure Blindness: A Road Towards Personalized Artificial Tissue.” Current Stem Cell Reports (2015): 1-13. http://download.springer.com/sta…
  2. Salero, Enrique, et al. “Adult human RPE can be activated into a multipotent stem cell that produces mesenchymal derivatives.” Cell stem cell 10.1 (2012): 88-95. http://ac.els-cdn.com/S193459091…
  3. Thomson, James A., et al. “Embryonic stem cell lines derived from human blastocysts.” science 282.5391 (1998): 1145-1147. http://www.biolchem.ucla.edu/lab…
  4. Nakano, Tokushige, et al. “Self-formation of optic cups and storable stratified neural retina from human ESCs.” Cell stem cell 10.6 (2012): 771-785. http://ac.els-cdn.com/S193459091…
  5. Nazari, Hossein, et al. “Stem cell based therapies for age-related macular degeneration: The promises and the challenges.” Progress in retinal and eye research 48 (2015): 1-39.
  6. Forest, David L., Lincoln V. Johnson, and Dennis O. Clegg. “Cellular models and therapies for age-related macular degeneration.” Disease models & mechanisms 8.5 (2015): 421-427. http://dmm.biologists.org/conten…
  7. Streilein, J. Wayne. “Ocular immune privilege: the eye takes a dim but practical view of immunity and inflammation.” Journal of leukocyte biology 74.2 (2003): 179-185. http://www.jleukbio.org/content/…
  8. Schwartz, Steven D., et al. “Embryonic stem cell trials for macular degeneration: a preliminary report.” The Lancet 379.9817 (2012): 713-720. https://www.ocata.com/uploads/sc…
  9. Schwartz, Steven D., et al. “Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies.” The Lancet 385.9967 (2015): 509-516.http://www.retinaitalia.org/wp-c…
  10. Kode, Jyoti A., et al. “Mesenchymal stem cells: immunobiology and role in immunomodulation and tissue regeneration.” Cytotherapy 11.4 (2009): 377-391. https://www.researchgate.net/pro…
  11. Singer, Nora G., and Arnold I. Caplan. “Mesenchymal stem cells: mechanisms of inflammation.” Annual Review of Pathology: Mechanisms of Disease 6 (2011): 457-478.
  12. Mead, Ben, et al. “Stem cell treatment of degenerative eye disease.” Stem cell research 14.3 (2015): 243-257. http://ac.els-cdn.com/S187350611…
  13. Liao, Jo-Ling, et al. “Molecular signature of primary retinal pigment epithelium and stem-cell-derived RPE cells.” Human molecular genetics 19.21 (2010): 4229-4238. http://hmg.oxfordjournals.org/co…

https://www.quora.com/Is-there-a-way-to-regenerate-or-repair-retina-cells/answer/Tirumalai-Kamala

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