stem cells and regenerative medicine

• Stem cells


  Can provide a fresh supply of differentiated cells when needed
• Types of stem cells

  • Totipotent: can make all cell types
  • Pluripotent: can make many cell types
  • Multipotent: can make a few cell types
• Stem cells in humans have only a limited capacity to deal with some injuries
• Stem cells tend to enter senescence with human aging, and will be 'exhausted'. So, repair becomes harder and harder as we get older
• Planarians


  • Small freshwater flatworms that can regenerate a completely new animal from a small fragment taken from almost anywhere in the body
  • Have the same tissues as other animals (gut, nerve cells, eyes, musculature), but with a unique regenerative capacity
• Neoblasts


  Planarians' stem cells, which are widely distributed throughout the body and can provide fresh, new cells at almost any location
• 1/5 of planarians' cells are stem cells (neoblasts)
• Planarian regeneration


  Stem cells (blue) accumulate near site of amputation, giving rise to new progeny cells (green) that allow for growth at the regenerating ends
• Neoblasts


  Totipotent, as they can give rise to all of the new cells in a planarian upon transplant
• Newt limb regeneration


  • Amputated limbs regrow in a process that resembles normal development: First form a blastema, which resembles an embryonic limb bud, then the blastema grows and cells differentiate to form a correctly patterned limb
  • Stem cells are multipotent, as the muscle stem cells only make new muscle
• In leukemia and lymphoma, a patient's own stem cells cannot replenish a healthy stock of blood cells
• Following irradiation, hematopoietic stem cells from a healthy donor can be transplanted into a disease patient, and allow for the creation of new healthy blood
• Epidermal (skin) stem cells from a healthy region of a burn patient can be cultured and used to repopulate the damaged body surface
• Neural stem cells


  • Active neural stem cells do exist in mammals, and when isolated and cultured, they form neurospheres (clusters of stem cells, glia and neurons) that can be propagated and transplanted back into the brain, where they can be successfully incorporated, to perhaps restore functional cells
• Parabiotic mice


  Have joined circulatory systems, so they share systemic factors
• Parabiotic pairings


  • Young-old (heterochronic)
  • Young-young; old-old (isochronic)
• Muscle stem cells become more active in old mice receiving young blood
• "Young blood" may enhance regenerative potential of other tissues
• Parabiotic pairings are not absolutely required; the transfer of young blood to an old mouse is sufficient (and allows for behavioral measurements, such as learning tasks)
• Memory was assessed using a Radial Arm Water Maze, and improved memory is thought to be due to improved neural stem cell function
• There are clinical trials moving forward looking at "young blood" transfusions and Alzheimer's patients
• Cells remain largely faithful to their origins, and cannot give rise to other cells types. Thus, stem cells of a human are limited in what cell types they can make.
• Making cells more pluripotent would obviously create a higher regenerative potential.
• If a nucleus of a differentiated cell is transplanted to an oocyte, the resulting hybrid can create a whole new organism.
• Reprogramming of a transplanted nucleus must involve dramatic changes to gene expression (as the nucleus was originally expressing a tissue-specific program, but becomes totipotent)
• Embryonic stem cells


  Derived from the inner cell mass, can in theory generate any cell of the body (even in vitro)
• Embryonic stem cells injected into the inner cell mass of another embryo can give rise to new tissues
• Therapeutically, this is quite powerful, because in theory cells with normal or repaired genes can be reintroduced into embryos that would otherwise develop into diseased individuals
• Embryonic stem cells


  • Must not enter senescence; they have very high telomerase activity (in contrast to differentiated somatic cells)
  • Have a specific gene expression program that is unique from differentiated cells, which exhibit tissue-specific expression
• Forced expression of four ES cell-specific transcription factors (Oct4, Sox2, Klf4, and Myc) can convert differentiated somatic cells into induced pluripotent stem cells (iPS cells)
• iPS cells


  Cells that are similar to ES cells, derived from differentiated cells
• iPS cells can allow for the generation of patient-specific cells of many types
• Different culturing conditions can push iPS or ES cells along a different developmental path (say, to a cell type that is hard to isolate)
• If the iPS cells are derived from a certain individual, these cells will be just like the cells in that person's body
• iPS cells can be used to test drugs for patient-specific conditions
• Gene editing technology can be utilized to correct a disease-causing mutation in iPS cells from a patient, and the edited iPS cells could then be induced to differentiate, and transplanted back into the patient
• In 2014, a Japanese woman in her 70s became the first human to receive iPS cell-derived tissues in the hope of correcting age-related macular degeneration
• The reprogramming process also appears to be rejuvenating, as telomeres of proliferating and senescent cells from 74-year-old individuals increase after iPS cell reprogramming
• Markers of aging (such as protein aggregates) are reversed with each new generation in the soma-germline cycle