Retinal Vitreous Resource Center: Professional

Bench Research

Topic: Stem Cells

Types of Stem Cells

  1. Induced pluripotent stem cells (iPS cells)
  2. Human embryonic stem cells (hESC)
  3. Human parthenogenetic stem cell (hpSC) lines
  4. Adult stem cells
  5. Hematopoietic stem cells
  6. Neural stem cells
  7. Pluripotent adult stem cells (umbilical cord blood)
  8. Mesenchymal stem cells (non-hematopoietic)
  9. Adipose derived regenerative stem cells

Types of stem cells gaining relevance to cell-based therapy for retinal degenerative diseases:

  1. Induced pluripotent adult stem cells (IPS cells)
  2. Human embryonic stem cells (hES cells)
  3. Human parthenogenetic stem cell (hpSC) lines
  4. Hematopoietic stem cells
  5. Adult stem cells

Induced Pluripotent Stem Cells (IPS cells)

Induced pluripotent stem cells derived from epithelial cells are not adult stem cells, but rather reprogrammed epithelial cells with pluripotent capabilities using genetic reprogramming with protein transcription factors. Pluripotent stem cells equivalent to embryonic stem cells have been derived from human adult skin tissue.

Shinya Yamanaka — Kyoto University in Japan — Adult Skin Tissue used transcription factors
OCT 3/4    SOX 2    C-MYC    LIN 28

James Thompson — University of Wisconsin — Madison — Human Foreskin used transcription factors
OCT 4    SOX 2    Nanog    LIN 28

Reprogrammed human skin cells have behaved almost exactly like embryonic stem cells. They return the cell to an embryonic-like state. Requires use of a gene-altered virus. Scientists had to use potentially dangerous viruses to introduced the four genes into the mouse cells. Researchers are now trying to find a benign virus and there are four ways being developed to do this.

Most promising methods to find benign virus vectors:

  • James Thomson, University of Wisconsin
    • Free-floating plasmid genes that don't enter nucleus
  • Kuong-Soo Kim, Harvard
    • Skin cells treated with proteins from cancer genes that do not enter nucleus
  • Two others leave traces of cancer gene in cell
    • R. Jaenisch, MIT
    • K. Kasi, University of Edinburgh and A. Nagy, Toronto

Human Embryonic Stem Cells (hESC)

  • Embryonic stem cells are derived from the inner cell mass of the developing blastocyst.

  • These cells ordinarily are destined to generate an individual, but under laboratory conditions, they develop from eggs that have been fertilized in vitro and then donated for research purposes with informed consent of the donors.

  • They are not derived from eggs fertilized in a woman's body.

  • Human embryonic stem cells have been used to grow RPE cells.
    • However, delivery of the RPE cells and the potential rejection of the cells remains problematic.
  • Dennis O. Clegg and Ray Lund
    • Derived RPE from hESC and showed rescue of visual function in dystrophic RCS rats
  • Masayo Takayashi
    • ES cell differentiation into neural retinal precursors which have the competence of generating cells with the photoreceptor phenotype.
  • Pete Coffey and Pfizer
    • hES cells to make patch of cells 3x6 mm of retinal pigment epithelium. Probably a seven-year effort.
  • R.E. MacLaren
    • Transplanted neural suspension of proliferative progenitor cells from postnatal day 1 mouse into the subretinal space of defective litter mates and showed appropriate synaptic connection and visual function.
  • Advanced cell technology, Lanza, and Ray Lund
    • hESC-derived retinal pigment epithelial (RPE) cells
  • Tsang and Del Priore
    • Showed that hESC can be coaxed to express markers for neural cells and photoreceptors
  • Lamba
    • Using a mixture of retinal cell types derived from hESCs demonstrated that stem-derived photoreceptors restores some cell visual function in Crx-deficient mice
  • D.M. Gamm
    • Human iPS and hESC have the potential to provide comprehensive model systems for the earliest stages of human ontogenesis

Human Parthenogenetic Stem Cell (hpSC) Line

  • These cells are derived from parthenogenetic blastocytes.

  • Stimulation of oocyte by ionomycin which acts like sperm and gives rise to "virgin birth."

  • This technique creates immune-matching cells to common immune types for transplantation, thereby reducing the chance of transplant rejection among a large segment of the population.

  • It gives all three embryonic germ layers.

  • Because they are created from unfertilized human eggs, they do not require the destruction of human embryos.

  • A recent press release by International Stem Cell Corporation stated, "We are developing intact retinal layers."

  • Have developed RPE cell lines

  • Have developed neural retina cell lines

  • Discussions of combining both for human trials

Hematopoietic Stem Cells

  • Hematopoietic stem cells are found in bone marrow and give rise to all the blood cell types.

  • Volker Enzmann
    • Bone marrow derived stem cells form retinal pigment epithelium
    • A critical area of research is to define the optimum milieu in which to promote the potential for repair
    • For regenerative medicine to be successful, the key point is to compare physiological properties of stem cells with directing the differentiation into the desired cell types via environmental cues

Adult Stem Cells

  • Adult stem cells are undifferentiated cells found throughout the body after embryonic development that divide to replenish dying cells and to regenerate damaged tissue.

  • Also known as "somatic stem cells", they can be found in children as well as adults.

  • Unlike embryonic stem cells, the use of adult stem cells for research and therapy is not controversial, because production of the adult stem cell does not require the creation or destruction of an embryo.

  • Unlike embryonic stem cells, the adult stem cells are often restricted to certain lineages.

  • Adult stem cell treatments have been used for many years to treat successfully leukemia and related bone/blood cancers through bone marrow transplants.

  • Masayo Takahashi
    • Single pigmented ciliary margin cells form rod photoreceptors
    • Iris tissue in adult mammalian eye gives rise to cells expressing neuronal antigens
  • G. Astrid Limd, PhD, BSc, Msc
    • Like zebrafish, adult human retina harbors a population of Müller cells with stem cell characteristics
  • Dong F. Chen
    • Injected glutamate and aminoadipate into the eye which triggered the dormant Müller cells to transform into progenitor cells, a more mature stem-like cell that generated new retinal cells

Predictions for clinical usefulness:

  • Three dimensional product of stem cells in a sheet with neural retinal together with its retina pigment epithelium needs to be obtained

  • Time frame probably 10-15 years

  • A mouse is not a human
    • Looks like retina
    • Does it function like a human retina?
  • Practical medical applications are years away for stem cell-derived products

  • FDA safety issues
    • Site dependent toxicities
    • Migration effect
    • Rogue cells are clinical hazard teratomas and terato-carcinomas
    • Difficulty predicting clinical effectiveness reliably
    • In preclinical studies, identify product characteristics associated with positive outcomes
    • Preclinical proof-of-concept needs to be particularly strong
  • Human subjects should not be "exposed to an unreasonable and significant risk of illness or injury"

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