Jessica Chen Figure 2

In the year 2013, there has been a plethora of advances made in the use of stem cells to regenerate organs, which offer promises in the treatment of human diseases. Among them is the identification of a population of stem cells in zebrafish that can regenerate damaged cone cells of the retina [1, 2]. Cone cells are visual receptor cells that are responsible for high acuity and colored vision in humans. This finding offers hope that one day, stem cell therapy may be used to regenerate damaged cones, and thus, return daylight vision to patients diagnosed with retinal degenerative diseases such as retinitis pigmentosa. However, despite the potential of the stem cell field in improving patients’ life, there remain obstacles to be overcome before advances made in the laboratory can be translated into routine treatment options.

Categories of stem cells

Stem cells are unspecialized cells that are identified based on their ability to both self-renew (make copies of themselves through cell divisions) and give rise to multiple specialized cell types. The specialized cells subsequently migrate from their place of origin to populate the tissues of the body.  The potency of the stem cell is determined by the categories of different cell types it can give rise to (Figure 1). Totipotent stem cells have the potential to generate a whole (“toti-”) embryo, and only exist during the earliest stages of embryonic development (between fertilization and the 16-cell stage). Currently, these cells cannot be cultured in the laboratory. Pluripotent stem cells have the potential to generate many (“pluri-“) cell types. Embryonic stem cells derived from the blastocyst stage embryo (5 days after fertilization) belong to this category. Multipotent stem cells have the potential to generate several (“multi-“) cell types, often those that are restricted to a particular tissue and/or organ. Many stem cells derived from adult tissues belong to this category [3]. A good example is hematopoietic stem cells (HSCs) found in the bone marrow, which have the potential to generate all blood cells including red blood cells, white blood cells and platelets [4]. Another category of stem cells that has been established in a laboratory environment are induced pluripotent stem cells (iPS cells), which are adult cells that have been engineered to revert back to a pluripotent state under laboratory conditions [3].

Figure 1: Origin and specialization of stem cells. Images obtained from http://openclipart.org and http://www.shutterstock.com.

 Hematopoietic stem cells in bone marrow transplant

Several decades ago, HSCs were discovered to have the ability to generate all blood cell types and repopulate the entire vascular system. Transplant experiments in mice have identified the bone marrow as a source of HSCs, as bone marrow from a donor mouse was able to repopulate the entire vascular system of a recipient mouse whose HSCs have previously been destroyed by irradiation [3, 5]. With the development of hematopoietic stem cells well-characterized, bone marrow is currently being used in cell replacement therapy for human cancers, such as leukemia and lymphoma. In leukemia patients undergoing chemotherapy and/or radiation therapy, the HSCs of the bone marrow are killed as a side effect. Therefore, bone marrow transplantation is often used as a mean to replenish the healthy cells and bone marrow of the patient upon completion of chemotherapy and/or radiation therapy [6].

The use of stem cells in trachea transplantation

In 2008, a multnational collaboration of scientists and medical professionals, led by Stockholm-based surgeon Dr. Paolo Macchiarini, successfully pioneered the first tissue-engineered airway replacement to restore lung function in humans. The recipient of the windpipe was a 30-year old woman with end-stage left-main bronchus malacia (i.e. collapse of the airways) due to tuberculosis infection. Normally, rings of cartilage encircle the windpipe and keep it from collapsing during respiration. These cartilage rings weaken and collapse in patients with bronchus malacia. In this treatment, the mesenchymal stem cells (another type of adult multipotent stem cell) from the bone marrow of the patient were harvested and directed to mature into cartilage cells. The windpipe from a transplant donor was completely removed of all cells and served as a scaffold for the repopulation of the patient-derived cartilage cells. Finally, the tissue-engineered windpipe is being transplanted into the patient [7] (Figure 2). Since the cartilage cells lining the windpipe were engineered using stem cells from the patient, there was no concern of immune rejection [8]. In the 5-year follow-up of this patient, the doctors found that the transplanted windpipe maintained proper function and the left lung was capable of normal gas exchange [9].

Figure 2: Schematic of tissue-engineering process for trachea transplantation. Modified from <http://news.bbc.co.uk/2/hi/7735696.stm>. Images obtained from http://openclipart.org and http://www.shutterstock.com.

 

While the above patient is able to have a relatively normal life, her success story is shadowed by the death of a 2-year old girl born without a trachea (tracheal agenesis) who underwent a similar transplantation procedure in April 2013. Though the tissue-engineered windpipe was functioning properly, the patient passed away less than 3-months post-surgery due to lung complications [10]. The differences in the outcomes of such transplantation surgeries remind us that although the field of regenerative medicine has tremendous potential in improving patients’ quality of life, hurdles remain in the use of these technologies.

Overcoming challenges

 

Some of the research being pursued in the field of regenerative medicine addresses the following challenges [3]:

  1. Safety in translation from bench to bedside. Tumor formation is a risk of stem cell therapies because the mechanisms governing the growth of stem cells resemble that of cancer cells [11]. Therefore, the methods by which scientists identify, isolate, and direct stem cells toward a particular cell type need to be standardized. In addition, the standardization of protocols may facilitate the commercial development of stem cell therapies and allow for more accurate evaluation of these therapies [12].
  2. Minimization of transplantation-induced immune response through personalized medicine. A major risk associated with transplantation surgeries is immune rejection of foreign organs. This can be remediated by using organs derived from the patients’ own stem cells, as in the trachea transplantation mentioned above.
  3. Functional integration of derived cells into the host tissue. While scientists have discovered methods to direct human stem cells to become a particular cell type, the contribution of these cells to the regeneration of tissues is dependent on its ability to successfully integrate into the target tissues and function in cooperation with the already existing host cells.

Despite the obstacles that remain to be overcome, the compilation of discoveries each year that revels in the newly identified cell types, tissues, and organs that can be generated in a laboratory setting give hope of the impact resulting from the high-risk endeavors scientists are currently undertaking.

Jessica W. Chen is a PhD student in the Biological and Biomedical Sciences Program at Harvard University.

References

  1. “Zebrafish may hold the answer to repairing damaged retinas and returning eyesight to people.” Science Daily, 31 Jan 2013. <http://www.sciencedaily.com/releases/2013/01/130131121308.htm>
  2. Faser B, DuVal MG, Wang H, Allison WT, 2013. Regeneration of cone photoreceptors when cell ablation is primarily restricted to a particular cone subtype. PLOS ONE, 8(1): e55410.
  3. “Stem cell facts.” International Society for Stem Cell Research, 2011. <http://www.isscr.org/docs/default-source/isscr-publications/isscr_11_stemcellfactbrch_fnl.pdf?sfvrsn=2>
  4. “Hematopoietic Stem Cells.” In Stem Cell Information. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2011. <http://stemcells.nih.gov/info/scireport/pages/chapter5.aspx>
  5. Spangrude GJ, Heimfeld S, Weissman IL, 1998. Purification and Characterization of mouse hematopoietic stem cells. Science, 241(4861): 58-62.
  6. “Bone marrow transplantation and peripheral blood stem cell transplantation.” In National Cancer Institute Fact Sheet. <http://www.cancer.gov/cancertopics/factsheet/Therapy/bone-marrow-transplant>
  7. Macchiarini P, Jungebluth P, Go T, Asnaghi MA, Rees LE, Cogan TA, Dodson A, Martorell J, Bellini S, Parnigotto PP, Dickinson SC, Hollander AP, Mantero S, Conconi M, Birchall MA, 2008. Clinical transplantation of a tissue-engineering airway. The Lancet, 372(9655): 2023-2030.
  8. “Unique method behind transplant of artifical trachea.” In Karolinska Institutet Press Release, 24 Nov 2011. <http://ki.se/ki/jsp/polopoly.jsp?d=2637&a=133222&l=en&newsdep=2637>
  9. Gonfiotti A, Jaus MO, Barale D, Baiguera S, Comin C, Lavorini F, Fontana G, Sibila O, Rombola G, Jungebluth P, Macchiarini P, 2013. The first tissue-engineered airway transplantation: 5-year follow-up results. The Lancet.
  10. 10. Katie Moisse. “Girl dies after groundbreaking trachea transplant.” In ABC World News, 8 July 2013. <http://abcnews.go.com/Health/girl-dies-groundbreaking-trachea-transplant/story?id=19604605>
  11. 11. Herberts CA, Kwa MSG, Hermsen HPH, 2011. Risk factors in the development of stem cell therapy. J Transl Med, 9:29.
  12. 12. Shen H, 2013. Stricter standards sought to curb stem-cell confusion. Nature  499: 389.

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