Stem Cells and Biomaterials for Regenerative Medicine

Stem Cells and Biomaterials for Regenerative Medicine addresses the urgent need for a compact source of information on both the cellular and biomaterial aspects of regenerative medicine. By developing a mutual understanding between three separately functioning areas of science—medicine, the latest technology, and clinical economics—the volume encourages interdisciplinary relationships that will lead to solutions for the significant challenges faced by today's regenerative medicine. Users will find sections on the homeostatic balance created by apoptosis and proliferating tissue stem cells, the naturally regenerative capacities of various tissue types, the potential regenerative benefits of iPS-generation, various differentiation protocols, and more.

Written in easily accessbile language, this volume is appropriate for any professional or medical staff looking to expand their knowledge with regard to stem cells and regenerative medicine.

• Arms readers with key information on tissue engineering, artificial organs and biomaterials, while using broadly accessible language
• Provides broad introduction to, and examples of, various types of stem cells, core concepts of regenerative medicine, biomaterials, nanotechnology and nanomaterials, somatic cell transdyferentiation, and more
• Edited and authored by researchers with expertise in regenerative medicine, (cancer) stem cells, biomaterials, genetics and nanomaterials

• Language: English
• Publisher: Academic Press
• Release date: Nov 7, 2018
• ISBN: 9780128122785

Book preview

Chapter 1

Introduction and Historic Perspective

Karolina Bakalorz*; Laura D. Los†; Emilia Wieche懠   ⁎ Faculty of Chemistry, Silesian University of Technology, Gliwice, Poland

† LinkoCare Life Sciences AB (Ltd), Linköping, Sweden

‡ Department of Clinical and Experimental Medicine (IKE), Division of Cell Biology, Linköping University, Linköping, Sweden

Regenerative medicine is a relatively young field of multidisciplinary research that involves replacing, repairing, or regeneration of impaired body organs, tissues, and cells. The first mentions about regenerative medicine come most likely from the paper The future of multihospital systems written by a recognized futurist and acknowledged authority on the changing American healthcare system, namely, Dr. Leland Kaiser. Already in 1992, he paid attention to a new branch of medicine that would influence the cure for chronic diseases and regenerate tired and failing organ systems [1]. The fascination of Prometheus’s liver that was able to regenerate in a short time after being eaten by an eagle or the regrowth of salamandra’s (Ambystoma mexicanum) amputated limb has become an inspiration for the current regenerative medicine [2]. In the case of a serious trauma or disease, transplantation of the missing or impaired organ is the only salvation for the patients. However, due to the shortage of organ donations and severe side effects of lifelong immunosuppression, the regenerative approach is currently gaining importance [3, 4]. It is likely that regenerative medicine will complement and then replace traditional transplantology in the near future.

There are several approaches, which are endeavoring to aid the objective of regenerative medicine. Nowadays, the progress of rapidly evolving regenerative medicine field is mainly associated with stem-cell-based therapy and tissue engineering [5]. Stem cells are undifferentiated cells, which possess unlimited capability to divide, self-renew, and differentiate into other types of cells within the body. The differentiation potential of stem cells during the in vivo maturation of the zygote goes down; therefore, the blastocyst-derived pluripotent embryonic stem cells have a huge regenerative potential and are a subject of extensive research [6, 7]. However due to their implication in carcinogenesis (teratoma formation), immune intolerance (external source; allogenic) as well as ethical issues (embryo-derived), the new strategies to obtain autologous source of stem cells are in progress. Several years of research on cloning of mammals and embryonic stem cells have allowed the identification of genes, which are responsible for the pluripotency of cells. In 2006, the breakthrough discovery in stem cell research was presented by Shinya Yamanaka from the Kyoto University and had been awarded the Nobel prize in physiology or medicine in 2012. He has shown that genetically modified somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) and they closely resemble embryonic stem cells, which might overcome the controversy with destruction of embryos [8]. Nevertheless, the major barrier facing clinical applications of iPSCs, besides their implication in teratoma formation, is use of viral vectors and recombinant DNA in order to express the pluripotent-cell-specific transcription factors during reprogramming. The new technologies are evolving and include among others the use of recombinant-cell-penetrating peptides and direct transfection of synthetic mRNA, which encode appropriate transcription factors [9, 10]. Furthermore, successful attempts to create various types of differentiated cells from fibroblasts without passing through the stem cell state (transdifferentiation) have been performed [11–14].

Unfortunately, only a small population of transplanted stem cells usually survive in the given microenvironment, and only those cells are capable of further differentiation. The classical injections of cellular suspension in saline vehicles are not an optimal therapeutic approach and in most of the cases < 10% of transplanted cells is retained in the target site [15]. The important issue is to create a unique microenvironment capable of supporting implanted cells in signaling molecules, growth factors, and hormones. A good carrier of such substances is biomaterial-based scaffold, which additionally provides a mechanical support for the cells [16–18]. Tissue engineering is a branch of regenerative medicine and the advances in the development of biomaterials and biomaterial scaffolds in combination with stem cells are capable of promoting regeneration [5, 18].

Regenerative medicine and stem cells give a great hope in the treatment of currently incurable diseases. During the last years, a number of new strategies to efficiently obtain and maintain certain types of stem cells for various treatments such as neurodegenerative diseases, heart disease and osteoporosis have been described [19–21]. However, the yield of in vitro stem cell production and their propensity to induce tumors upon transplantation is a serious challenge for the researchers. We can still benefit from the current knowledge in terms of using stem cells for disease modeling and drug screening on the way to personalized medicine [22, 23].

Despite so many efforts, there are not many stem-cell-based therapies approved that are commercially available [18, 24]. Since the pioneer bone marrow transplant between a related donor and recipient, which was performed in 1956 by Dr. E. Donnall Thomas in New York, this is still the most widely used stem-cell therapy nowadays. Moreover, the attempts to transplantation of artificial tissues and organs on routine clinical settings are rapidly developing. The best described examples involve biomaterial-based bladder reconstruction, vascular regeneration, skin substitutes, tissue-engineered trachea, and artificial corneas [25–33].

References

[1] Kaiser L.R. The future of multihospital systems. Top Health Care Financ. 1992;18(4):32–45.

[2] Kragl M., et al. Cells keep a memory of their tissue origin during axolotl limb regeneration. Nature. 2009;460(7251):60–65.

[3] Saidi R.F., Hejazii Kenari S.K. Clinical transplantation and tolerance: are we there yet?. Int J Organ Transplant Med. 2014;5(4):137–145.

[4] Power C., Rasko J.E. Whither prometheus’ liver? Greek myth and the science of regeneration. Ann Intern Med. 2008;149(6):421–426.

[5] Katari R., Peloso A., Orlando G. Tissue engineering and regenerative medicine: semantic considerations for an evolving paradigm. Front Bioeng Biotechnol. 2014;2:57.

[6] Mahla R.S. Stem cells applications in regenerative medicine and disease therapeutics. Int J Cell Biol. 2016;2016:6940283.

[7] Passier R. Potential of human embryonic stem cells in regenerative medicine. Horm Res. 2003;60(Suppl. 3):11–14.

[8] Takahashi K., Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–676.

[9] Heng B.C., Fussenegger M. Integration-free reprogramming of human somatic cells to induced pluripotent stem cells (iPSCs) without viral vectors, recombinant DNA, and genetic modification. Methods Mol Biol. 2014;1151:75–94.

[10] Rony I.K., et al. Inducing pluripotency in vitro: recent advances and highlights in induced pluripotent stem cells generation and pluripotency reprogramming. Cell Prolif. 2015;48(2):140–156.

[11] Xu Z., et al. Direct conversion of human fibroblasts to induced serotonergic neurons. Mol Psychiatry. 2016;21(1):62–70.

[12] Son E.Y., et al. Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell. 2011;9(3):205–218.

[13] Xu A., Cheng L. Chemical transdifferentiation: closer to regenerative medicine. Front Med. 2016;10(2):152–165.

[14] Guo J., Wang H., Hu X. Reprogramming and transdifferentiation shift the landscape of regenerative medicine. DNA Cell Biol. 2013;32(10):565–572.

[15] Mooney D.J., Vandenburgh H. Cell delivery mechanisms for tissue repair. Cell Stem Cell. 2008;2(3):205–213.

[16] Edgar L., et al. Heterogeneity of scaffold biomaterials in tissue engineering. Materials (Basel). 2016;9(5) pii:E332.

[17] Jammalamadaka U., Tappa K. Recent advances in biomaterials for 3D printing and tissue engineering. J Funct Biomater. 2018;9(1) pii: E22.

[18] Mao A.S., Mooney D.J. Regenerative medicine: current therapies and future directions. Proc Natl Acad Sci USA. 2015;112(47):14452–14459.

[19] Lunn J.S., et al. Stem cell technology for neurodegenerative diseases. Ann Neurol. 2011;70(3):353–361.

[20] Tompkins B.A., et al. Preclinical studies of stem cell therapy for heart disease. Circ Res. 2018;122(7):1006–1020.

[21] Phetfong J., et al. Osteoporosis: the current status of mesenchymal stem cell-based therapy. Cell Mol Biol Lett. 2016;21:12.

[22] Avior Y., Sagi I., Benvenisty N. Pluripotent stem cells in disease modelling and drug discovery. Nat Rev Mol Cell Biol. 2016;17(3):170–182.

[23] Suh W. A new era of disease modeling and drug discovery using induced pluripotent stem cells. Arch Pharm Res. 2017;40(1):1–12.

[24] Reisman M., Adams K.T. Stem cell therapy: a look at current research, regulations, and remaining hurdles. P&T. 2014;39(12):846–857.

[25] Atala A., et al. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet. 2006;367(9518):1241–1246.

[26] Lam Van Ba O., et al. Bladder tissue engineering: a literature review. Adv Drug Deliv Rev. 2015;82–83:31–37.

[27] Li S., Sengupta D., Chien S. Vascular tissue engineering: from in vitro to in situ. Wiley Interdiscip Rev Syst Biol Med. 2014;6(1):61–76.

[28] Shin'oka T., Imai Y., Ikada Y. Transplantation of a tissue-engineered pulmonary artery. N Engl J Med. 2001;344(7):532–533.

[29] Kurobe H., et al. Concise review: tissue-engineered vascular grafts for cardiac surgery: past, present, and future. Stem Cells Transl Med. 2012;1(7):566–571.

[30] Vig K., et al. Advances in skin regeneration using tissue engineering. Int J Mol Sci. 2017;18(4) pii:E789.

[31] Elliott M.J., et al. Stem-cell-based, tissue engineered tracheal replacement in a child: a 2-year follow-up study. Lancet. 2012;380(9846):994–1000.

[32] O'Leary C., et al. Respiratory tissue engineering: current status and opportunities for the future. Tissue Eng Part B Rev. 2015;21(4):323–344.

[33] Ghezzi C.E., Rnjak-Kovacina J., Kaplan D.L. Corneal tissue engineering: recent advances and future perspectives. Tissue Eng Part B Rev. 2015;21(3):278–287.

Chapter 2

Stem Cells

Marek J. Łos*,†,‡;

Aleksandra Skubis#,§; Saeid Ghavami¶,∥    ⁎ Małopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland

† LinkoCare Life Sciences AB (Ltd), Linköping, Sweden

‡ Center for Molecular Biophysics, UPR4301 CNRS CS80054, Orleans Cedex 2, France

§ Department of Molecular Biology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland

¶ Department of Human Anatomy and Cell Science, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada

‖ Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran

# Department of Cytophysiology, Chair of Histology and Embryology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland

Abstract

The chapter discuses definition of stem cells and their classification based on differentiation potential and origin. Stem cells are type of unspecialized cells defined on properties as ability to self-renewal, unlimited divisions, and potential to differentiate into more specialized cells. Stem cells are the foundation of tissue homeostasis and regeneration of organisms. Most of the time, they stay inactive until they get prompted to divide by physical or chemical factors. Stem cells can be classified, based on their plasticity. They can be totipotent, pluripotent, multipotent, oligopotent, and unipotent. Cells also can be classified based on the place of occurrence. In the following, we provide the description of characteristics of main types of stem cells, like embryonic stem cells, adult stem cells, and induced pluripotent stem cells. Embryonic stem cells are pluripotent, but they can be obtained only from preimplantation-stage embryos, which is controversial. Adult stem cells, also called somatic stem cells, are found in many tissues of adult body. Most often adult stem cells are multipotent, and their harvesting is associated with less ethical concerns, especially if they are being obtained from medical waste (tissues removed after surgery). Adult stem cells as hematopoietic stem cells or mesenchymal stem cells can be isolated from bone marrow, peripheral blood, or adipose tissue. Most (if not all) organs contain tissue specific stem cells. High expectations have been associated with induced pluripotent stem cells (iPS), which are similar in self-renewal capacities, morphology, growth kinetics, and gene expression to embryonic stem cells, but they are derived from somatic cells through genetic reprogramming.

Keywords

Regenerative potential; Embryonic stem cells; Induced pluripotent stem cells; Adult stem cells

Introduction

Stem cells are undifferentiated cells defined by two criteria: a potential to self- renewal and differentiate into multiple mature cell types. Self-renewal is reflected by their capacity to undergo multiple/limitless divisions [1, 2]. Several signaling pathways are involved in self-renewal of stem cells, that is, Notch, Wnt, and Hedgehog pathways or Polycomb family proteins [2]. Stem cells may replicate through two types of cell divisions: symmetric: (i) both daughter cells are identical as parent stem cells, and (ii) asymmetric, one of two cells is identical to parent stem cells and the second enters differentiation into more specialized cell lineage (Fig. 2.1).

Fig. 2.1 Asymmetric and symmetric division of stem cells.

Symmetric divisions assure repopulation of the niche of undifferentiated stem cells. Asymmetric divisions warrant preservation of the stem cell pool and maintain homeostasis within the given tissue [3, 4]. Differentiation of a subpopulation of stem cell descendants is crucial for the regeneration and repair of damaged tissues and organs in the body [2, 5].

Stem cell niches are located in specific anatomic microenvironment that allows for stem cells self-renewal and maintenance of their undifferentiated potential [6–8]. Stem cell niches are characterized by defined histologic environment, the availability of certain types of adhesion molecules, and often also the presence of supporting cells [8]. Each stem cell niche has organ-specific histologic features. As examples may serve, niche of hematopoietic stem cells (HSC) in trabecular bones, intestinal crypts in digestive tract, hair follicle bulge for regeneration of keratinocytes, hair, and sebaceous glands or subventricular zone of the cerebellum, and the subgranular zone of the hypothalamus is responsible for producing astrocytes [9–11].

Functionally, stem cell niches may be classified as either simple niche, complex niche, or storage niche (Fig. 2.2) [11]. In simple niche, stem cells adhere to each other through specific adhesion molecules, which lock stem cell in a place until proliferation signal is received. They are simple in structure and are typical for epithelial, digestive tissues, and gonads. Complex niches consist of stem cell interacting with other stem cells and differentiated partner cell, while forming large complexes of cells, which provide better regulatory control mechanisms than in a simple niche, i.e., subventricular zone neural stem cells reside in a complex niche. Storage niches are basically repositories of stem cells. There, the cells typically do not divide, instead they migrate from the niche after receiving signals specific signals. Hair follicle and niches storing melanoblast progenitors niche are examples of storage niche [11].

Fig. 2.2 Niche types: simple (A), complex (B), and storage (C). (Based on Ohlstein B, Kai T, Decotto E, Spradling A. The stem cell niche: theme and variations. Curr Opin Cell Biol 2004;16(6):693–9.)

Stem Cell—Potency

Stem cells could be classified according to their plasticity/regenerative potential into: totipotent, pluripotent, multipotent, oligopotent, and unipotent (Table 2.1) [5, 12].

Table 2.1