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Understanding Stem Cells, Part 1: Stem Cells 101

Stem cells are a promising regenerative medicine tool and treatment. So much information on stem cell research exists that sorting through the facts and the hype can be daunting. This post will focus on explaining stem cell basics: What are stem cells, and what are the different types? Here, we will focus on adult stem cells, also known as somatic stem cells, since these are most relevant to medical research and clinical use today.

Nearly every cell in the body has a specific purpose. When a fetus begins to develop, cells become specialized (or differentiated), developing structure and characteristics specific to carrying out a special function in the body.1 For example, heart muscle cells generate movement (i.e., heartbeat), and red blood cells contain hemoglobin so that they can transport oxygen throughout the bloodstream. Stem cells, on the other hand, are unspecialized (undifferentiated); they have the potential to become any type of cell.

There are different categories of stem cells. Most current research focuses on these stem cell types:

  • Totipotent—can form all cell types in the body. During embryonic development, totipotent stem cells differentiate into all of the different cell types in order to form a whole organism. Researchers have been able to take differentiated cells and return them to a state of totipotency. More work is needed to make totipotent cells clinically useful.
  • Pluripotent—are descended from totipotent stem cells and can form into almost all cell types. Pluripotent stem cells can form any type of cell derived from the three germ layers: endoderm (forms the inside lining of stomach, digestive tract, and lungs), mesoderm (forms blood, muscle, and bone), and ectoderm (forms the skin and nervous system.) Pluripotent stem cells naturally exist in the embryo.
  • Multipotent—more specialized than totipotent and pluripotent stem cells, multipotent cells can develop into several different somatic cell types. Multipotent stem cells give rise to various tissues and organs during development, and some of these stem cells remain in a state of dormancy (“quiescence”) within their specific tissue niches of the adult human body. Types of multipotent stem cells include:
    • Hematopoietic stem cells—form the components of the blood.
    • Mesenchymal stem cells—form bone, cartilage, muscle, and fat cells.
    • Neural stem cells—form the nervous system.
    • Epithelial stem cells—form cells in the digestive tract lining.
  • Oligopotent—can form a few different cell types. They are derived from multipotent stem cells, descending from hematopoietic stem cells. Examples:
    • Lymphoid cells—form several types of immune cells, such as B cells and T cells.
    • Myeloid cells—form red blood cells and white blood cells, among others.

As mentioned above, stem cells are found in the adult body within tissues such as blood, bone, skin, heart, and gut, as multipotent cells. It’s believed that the cells are located in a stem cell niche, or a specific area of each tissue. The number of niche-dwelling stem cells is relatively small. These cells may remain quiescent (undifferentiated) for a long time, until disease, injury, or normal body processes cause the need for differentiation.

Three main sources of these adult somatic stem cells are bone marrow, blood, and adipose, tissue. Research is being conducted on ways to grow larger numbers of adult stem cells outside the body. When experimental conditions in the laboratory are right, stem cells can be induced to become specialized cells that perform specific functions. This has important implications for regenerative medicine.

Inducing cells from a patient’s own body to grow into the specific tissue they need to receive could lead to tremendous medical advances, someday eliminating the need for allografts and organ transplants. In the lab, researchers have been able to manipulate adult somatic stem cells to become induced pluripotent stem cells, or iPSCs. Through forced expression of specific genes, transcription factors, and epigenetic factors, differentiated somatic cells can be de-differentiated or induced to return to a pluripotent state. Advances have been made in scientific research on therapeutic implications of iPSCs.

Another source of pluripotent stem cells is umbilical cord blood. Stem cells from umbilical cord blood can be saved just after birth, cryopreserved for later use, and stored in an umbilical cord blood bank.2 There are now commercialized injectable therapies using umbilical cord blood stem cells.

There are many exciting possible applications of the stem cell research now being performed in laboratories worldwide. One example of this involves limbal stem cells, or LSCs. LSCs are found in the limbus, the part of the eye where the cornea meets the sclera. Normally, these cells are used to regenerate the cornea, which has a very fast turnover rate of 1-2 weeks in the human body. If a person’s LSCs deteriorate or they do not have enough LSCs, their corneas degenerate and they will go blind. However, research suggests that if LSCs were transplanted into such an eye, the entire cornea would regenerate.3 Researchers have studied LSCs using experiments with mice, and were able to restore the cornea of mice with experimental blindness. These results are promising for regenerative medicine in humans. For more information about the applications of stem cell research, check out Part 2.

References:

Stem Cell Basics (2016). National Institutes of Health. Retrieved from https://stemcells.nih.gov/info/basics.htm.

Jawdat, Dunia (2016). Banking of Human Umbilical Cord Blood Stem Cells and Their Clinical Applications. In Abdelalim E. (ed.) Recent Advances in Stem Cells. Humana Press. Retrieved from https://link.springer.com/chapter/10.1007/978-3-319-33270-3_8.

Limbal Stem Cells for Treatment of Corneal Blindness (2017). Advanced Science News. Retrieved from http://www.advancedsciencenews.com/limbal-stem-cells-treatment-corneal-blindness/.

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3D Printed Tissues From Bench to Bedside

3D bioprinting has the potential to provide significant medical advances. For example, 3D printing of functional tissues and organs could someday alleviate shortages in organ availability and the problem of organ incompatibility. But where does the field stand today?

A look at the research benches of top labs can give us an idea. In this post we’ll take a look at CELLINK’s innovative inks and printers, ORGANOVO’s functional bioprinted tissues, Dr. Anthony Atala’s Wake Forest Institute for Regenerative Medicine, and the 3D printed cortical fibers line by Xtant Medical, 3Demin®.

CELLINK is the world’s first bioink company. A Swedish company founded in 2016, CELLINK solved problems for the tissue engineering community by commercializing hydrogel bioinks which can be used to 3D print cartilage, bone, skin, or muscle. CELLINK is also a top provider of bioprinters. It’s likely to be one of CELLINK’s printers in a researcher’s lab being used to create 3D printed allografts during experiments, as was the case of the 3D printed cartilage mentioned in the prior post. With the right raw materials, it’s possible to create multiple biologics scaffolds and structures, and CELLINK is at the forefront of bioink development.1

ORGANOVO creates functional, responsive bioprinted human tissue models for preclinical testing and drug discovery research. Their 3D bioprinted tissues remain viable and dynamic for more than 28 days in vitro.2 Their key architectural and functional features mimic natural function and provide important information for scientists.

Pharmaceutical companies conducting research can examine the effects of new compounds on ORGANOVO’s ExVive™ 3D bioprinted human tissues. This allows tissue-specific data to be collected to better predict human outcomes, lower total development time, and reduce costs.

For example, liver and kidney tissues can be used to evaluate drug exposure for both acute and chronic toxicity and metabolism studies.2 ORGANOVO is also working on developing functional, 3D tissues for implantation or delivery into the human body, with the intention of creating these tissue for use for repair or replacement of damaged or diseased tissues.3

The Wake Forest Institute for Regenerative Medicine is one of the nation’s top research labs working to translate scientific discoveries in 3D printing into clinical therapies. Led by Dr. Anthony Atala, a pioneer in medical tissue engineering, this interdisciplinary team is engineering more than 30 different replacement tissues and organs to develop curative cell therapies.4 Wake Forest was the first institution to successfully engineer laboratory-grown organs and implant them into humans: these were engineered bladders grown from the patient’s own cells.5

The fact is, all living tissues are composed of many different cell types arranged in a specific order that is essential to function. Therefore, when using 3D printing to create a tissue, precision is critical.6 Researchers at Wake Forest have designed their own inkjet bioprinter that can print kidney cells, and the binders to hold the cells together, into a 3D kidney prototype. This bioprinter could potentially be used to create a custom organ based on a CT scan and patient data. Their bioprinter is also being tested in the creation of other structured tissue, such as the ear.7

While 3D bioprinting of living, functional, clinically applicable tissues and organs remains the Holy Grail, there are much simpler examples of the technology already commercialized and in use today.  Bacterin’s 3Demin® line of demineralized cortical bone fibers is bioprinted into different shapes and sizes designed for specific surgical applications. The bioprinting process creates a porous, interconnected allograft that contains BMPs and other growth factors necessary to promote new bone formation. It is an osteoconductive demineralized cortical fiber matrix with osteoinductive potential that can be used as a stand-alone graft, or in combination with autologous bone, bone marrow, DBM putty, and other products.8

Bacterin’s production of customized bone implants using 3D printing technology was applied clinically during a mission sponsored by the World Craniofacial Foundation. In Zambia, a child named Grace Kabelenga was born with the most severe facial cleft in 40 years (Tessier 0-14), and a total absence of the bones separating her brain from her oral cavity.9 3D printed plastic prototypes allowed the team to simulate surgery and to create molds for custom bone implants. Bacterin’s 3Demin® bone allograft material was used to create custom 3D printed bone to serve as a “bandeau” to define the superior orbital rims above her eyes.10 This was combined with other Bacterin allografts and rhBMP2 to reconstruct missing parts of Grace’s skull.

Multiple surgeries have allowed Grace to function as a normal child would. Allografts.com members can view a video about the WCF mission on our portal. A slide deck is also available here.

3D printing for tissue engineering has the potential to provide incredible benefits to humankind if the technology can be developed to its full potential for medical applications.

If you missed it, you can read more about the history and applications of bioprinting here: 3D Printing in Tissue Engineering.

References:

1 CELLINK. (2017). BioX Printer. Retrieved from https://cellink.com/bioprinter/

2 ORGANOVO. (2017). 3D human liver tissue testing services. Retrieved from http://organovo.com/tissues-services/exvive3d-human-tissue-models-services-research/3d-human-liver-tissue-testing-services/

3 ORGANOVO. (2017). About ORGANOVO. Retrieved from http://organovo.com/about/about-organovo/

4 Wake Forest School of Medicine. (n.d.). Wake Forest Institute for Regenerative Medicine. Retrieved from http://www.wakehealth.edu/WFIRM/

5 Wake Forest Baptist Medical Center. (2006). Wake Forest physician reports first human recipients of laboratory-grown organs. Retrieved from http://www.wakehealth.edu/News-Releases/2006/Wake_Forest_Physician_Reports_First_Human_Recipients_of_Laboratory-Grown_Organs.htm

6 Wake Forest School of Medicine. (2017, September 6). Using 3D printing technology to print organs and tissue. Retrieved from http://www.wakehealth.edu/Research/WFIRM/Our-Story/Inside-the-Lab/Bioprinting.htm

7 Wake Forest School of Medicine. (2016, August 8). Replacement organs and tissues: Engineering a kidney. Retrieved from http://www.wakehealth.edu/Research/WFIRM/Research/Engineering-A-Kidney.htm

8 Bacterin. (2015). 3Demin Benefits. Retrieved from: https://xtantmedical.com/app/uploads/2016/09/3Demin_Brochure_Digital-14009B.pdf

9 3D Systems. (2016). Delivering the gift of a normal life. Retrieved from: https://www.3dsystems.com/sites/default/files/2016/cs_3ds_grace_kabelenga_0316_0.pdf

10 3D Systems. (2017). Delivering the gift of a normal life with 3D systems healthcare solutions. Retrieved from 3D Systems. Delivering the gift of a normal life with 3D systems healthcare solutions. Retrieved from https://www.3dsystems.com/learning-center/case-studies/delivering-gift-normal-life