different types of stem cells and other therapeutic cell types used in research and disease treatment

what are the types of stem cells?

• embryonic stem cells

• adult stem cells

• fetal stem cells

• umbilical cord stem cells

• somatic cell nuclear transfer (SCNT) stem cells

• induced pluripotent stem cells (iPS cells)

• parthenogenetic stem cells

• neural stem cells

what are embryonic stem cells?

• isolated from a blastocyst
• pluripotent: can differentiate into any cell type

what are adult stem cells?

• unipotent, multipotent differentiation
• 3 major categories: true adult stem cells, multipotent stgromal cells, progenitor cells

what are true adult stem cells?

• sometimes called tissue stem cells
• capable of long-term self-renewal
• maintain a specific tissue for life
• can generate multiple cell types within that tissue
• e.g. hematopoietic stem cells

what are multipotent stromal cells?

• sometimes called mesenchymal stem cells (MSCs)
• connective tissue-associated cells
• show multipotent differentiation in vitro (but in vivo stemness remains debated)
• often function through signaling and tissue support

what are progenitor cells?

• more differentiated than true stem cells
• limited self-renewal
• committed to a specific lineage
• e.g. endothelial progenitor cells (EPCs)

what are hematopoietic stem cells (HSCs)?

• in the bone marrow: mostly in the red bone marrow
• important examples of adult stem cells (multipotent)
• differentiate into myeloid and lymphoid progenitor cells, which then differentiate into innate immune cells (RBCs, erythrocytes), platelets, and adaptive immune cells (innate cytotoxic immunity)
• true stem cells

what are mesenchymal stromal cells (MSCs)?

• found in bone marrow as well as some other tissues
• mostly in the yellow bone marrow (stromal region): consists of connective tissue
• in in vitro studies, give rise to bone, cartilage, muscle, and several other tissues, but their exact functions in vivo are still not completely understood
• secrete key factors that support tissue repair and modulate immune responses

what are multi-lineage differentiating stress-enduring (Muse) cells?

• isolated as a subset of MSCs
• can be identified by specific cell surface markers
• make up only about 1-2% of MSCs
• studies suggest they may have pluripotency markers
• may also have more therapeutic potential than MSCs

what is the skin?

• important source of adult stem cells layers:
• skin barrier: outermost layer, contains dead keratinocytes
• basal layer: contains epidermal stem cells and other cell types
• epidermal stem cells will give rise to the keratinocytes

what are the adult stem cells in the intestine?

• crypt base columnar stem cells: give rise to enterocytes along with all epithelial cell types of the intestine; can replicate and differentiate
• enterocytes and other cell types: short half-life; form of protection
• paneth cells: involved in immunity

what are other examples of adult stem cells?

• spermatogonial stem cells: give rise to sperm (unipotent)
• hair follicle stem cells: give rise to cells that form the hair shaft (multipotent; give rise to multiple cell types in the hair shaft)
• muscle stem cells (MuSCs): ala skeletal muscle satellite cells; give rise to muscle cells after injury, muscle loss, etc. (unipotent)

what are fetal tissue cells?

• usually multipotent
• including stem and progenitor cells that maintain the rapid growth of the fetus in the first trimester, where primitive organs arre all in place
• taken from fetal tissue that contains a mix of cells, including stem and progenitor cells
• used as a good source of dopamine neurons for the potential treatment of Parkinson's disease

what are umbilical cord stem cells?

• the umbilical cord can be a good source of stem cells
• parents can choose to save the umbilical cord blood of their newborns
• these are stored in either private or public cord blood banks
• pros and cons to the storage of umbilical cord stem cells

what are the main types of stem cells and related cells in the umbilical cord and umbilical cord blood?

• hematopoietic stem cells: from cord blood within the vessels (vein and arteries)
• mesenchymal stromal cells: from the Wharton's jelly
• endothelial progenitor cells from the umbilical vein: can give rise to more endothelial cells

what are somatic cell nuclear transfer (SCNT) cells?

• may be pluripotent
• made from: a cell (an egg) from one animal and a nucleus (including DNA) from a cell (usually somatic) from another animal
• advantages of using nuclear transplant stem cells
• ethical issues

what is the process of the birth of Dolly the sheep?

1. one tissue cell donor and one donor who supplies unfertilized eggs

• cells from animal to be cloned are maintained in the lab so they do not grow/divide

1. nucleus is removed from cells
2. nucleus from tissue cell donor fuses with empty egg after electric current applied
3. the reconstructed embryo grows for 7 days

• produces ES cells that differentiate into SCNT cells

1. embryo's implanted into surrogate mother
2. reproductive cloning

• cloned animal is born with exact DNA as the tissue cell donor

what is reproductive cloning vs therapeutic cloning?

• SCNT was developed as a tool for derivation of stem cells (therapeutic cloning), but the technique has also been used successfully to clone animals (reproductive cloning)
• e.g. snuppy the hound: cloned from a single cell of an adult dog ear

what is SCNT technology with human cells?

• making SCNT cells from human cells was a major hurdle
• the first human SCNT was reported in 2004, but the work was found to be fradulent
• one hurdle was that the human embryos made with SCNTs stopped dividing at the 8-cell stage
• this had to do with premature exit from meiosis in the human oocytes
• this problem existed in other primates as well

how did scientists make human SCNT cells?

• conditions for making SCNTs were first optimized in primates
• this was repeated in human cells, where the donor cells were infant skin cells
• from this, scientists successfully made 4 pluripotent human stem cell lines (SCNTs) in 2013
• the infant had leigh syndrome, a genetic neurologic disorder, and the goal was to use the stem cells to study this disorder

what is the potential for adult SCNT cells?

• research models for diseases
• implantation back into human patients: cell replacement therapy, autologous therapy

what are telomeres?

• at the ends of chromosomes
• prevent the coding regions of chromosomes from losing nulceotides when cells divide
• in most somatic cells, they shorten each time a cell divides (due to lack of functional telomerase)
• chromsomes in somatic cells of older individuals generally have shorter telomeres than those in the cells of younger individuals

what is the issue with telomeres and SCNT cells?

• important question: in SCNT stem cell cloning, would telomere length in the resulting cells be the same as that of the telomeres of the donor?
• scientists found that during early embryonic development after SCNT, telomerase is often reactivated, and telomeres are lengthened, resulting in stem cells with longer telomeres than the donor cells
• this reactivation is variable across different studies and species

what are the ethical and political issues with SCNT cells?

• involves cloning techniques (though implanting the embryos into humans is not allowed by US law)
• involves destruction of an emrbyo

what are the downsides of SCNT cells?

• medical issues or side effects may result from reproductive cloning in cloned mice, there have been some examples of:
• damaged immune systems
• increase pneumonia and subsequent death
• increased development of tumors
• liver failure
• spontaneous abortions
• abnormal births
• shortened lifespans

what are induced pluripotent stem (iPS) cells?

• cells with stem cell characteristics, generated in the lab, from normal somatic cells
• in 2007, 3 groups (1 in Japan, 2 in US) generated ES-like cells by introducing 4 genes into adult skin cells
• the genes were introduced by retroviral infection, producing iPS cells

what are the 4 transgenes used to develop iPS?

• Oct3/4: transcription factor associated with many target genes implicated in maintenance of pluripotency
• Sox2: transcription factor necessary for embryonic development and for preventing ES cell differentiation
• C-Myc: transcription factor with many cellular functions; important for proliferation, oncogenic
• Klf4: transcription factor; its overexpression inhibits differentiation of ES cells

what are 2 new transgenes of iPS cells?

• nanog: transcription factor, normally found in embryonic stem cells; has a role in promoting pluripotency
• Lin28: an mRNA binding protein found in ES cells that has a role both in pluripotency and differentiation

what is the process of iPS cell development?

1. adult fibroblast cells are reprogrammed back into a pluripotent state

• by introducing specific transcription factors via retroviral infection

1. become iPS cells

• characterized by their ability to self-renew and differentiate into cells from all 3 germ layers

1. by applying specific growth factors and signals, scientists can guide these iPS cells to become specialized "daughter" cells

• e.g. cardiomyocytes, adipocytes, neural cells, pancreatic β-cells, hematopoietic progenitor cells

what are the advantages of using iPS cells?

• abolishes the need for embryos
• allows for personalized disease treatment
• can make genetically matched cells for autologous treatment, to avoid rejection

what are the challenges in the use of iPS?

• gene were introduced into cells using a retrovirus: can be dangerous, and in some cases, lead to cancer
• requires the expression of genes involved in cancer (c-Myc)
• takes time to generate cells
• there have been problems with slow growth and senescence of the cells
• iPS cells develop mutations over time, which may increase the risk of cancer
• for now, iPS cells are used mostly for research, rather than for treatment, though some clinical studies are also being started

how are iPS cells used in research?

• may be useful for modeling various diseases e.g. to study liver disease:
• skin fibroblasts were isolated from patients with inherited liver diseases
• these skin cells were made into iPS cells and cultured
• cells were differentiated into liver cells
• the cells took on chracteristics of the diseased livers of the patients

what are parthenogenetic stem cells?

• parthenogenetic egg activation involves the activation of unfertilized eggs: this requires an understanding of the biological mechanisms behind egg activation
• artifical egg activation and the generation of stem cells
• several types of chemicals can bring out the activation of metaphase II arrested eggs in culture, even in the absence of sperm, such as ethanol, electric currents, etc.
• these activated eggs can form a blastocyst but cannot form an embryo
• stem cells can be isolated from these blastocysts

what are neural stem cells (NSCs)?

• can have different meanings and origins
• refers to cells that can differentiate into neurons
• can come from various different sources, all of which arre termed NSCs

where can NSCs come from?

• iPS cells that are differentiated into neurons in vitro
• ES cells that are differentiated into neurons in vitro
• MSCs that are differentiated into neurons in vitro
• fetal stem cells from the fetal nervous system
• a small number of NSCs are present naturally in the brain throughout life (adult stem cells): give rise to olfactory neurons and some granule cells