© Springer International Publishing AG 2017
Stefano Gumina (ed.)Rotator Cuff Tear10.1007/978-3-319-33355-7_42Stem Cells in Rotator Cuff Healing
(1)
Department of Biomedical Science for the Health, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
Introduction
Rotator cuff (RC) tears represent the vast majority of shoulder injuries in adult patients and are a common contributing factor to shoulder pain and occupational disability, and their prevalence in the population is rising. Although surgical procedures to repair have evolved and improved over the past decades, a high rate of failure, which may require additional therapy or re-intervention, thus decreasing the patient’s quality of life, has been observed after RC repair.
In order to enhance tendon healing after arthroscopic repair, several biological strategies are being investigated. There is increasing interest in the application of stem cells to enhance tendon healing.
This chapter will examine current literature regarding the application of mesenchymal stem cells to improve tendon healing in animals and in a clinical setting.
Definition
Stem cells are defined as unspecialized cells that provide a self-renewing population and have the potential to differentiate into various adult cell types.
They serve as a repair system by being able to divide without limit to replenish other cells.
Types of Stem Cells
Stem cells can be classified by the extent to which they can differentiate into different cell types (potency):
Totipotent stem cells
Pluripotent stem cells
Multipotent stem cells
Unipotent stem cells
Totipotent stem cells (such as a fertilized egg) have the ability to generate all of the cell types in the body, as well as all of the cell types that make up the extra-embryonic tissues such as the placenta. Pluripotent stem cells (such as embryonic stem cells) develop about 4 days after fertilization. Pluripotent stem cells can generate all of the different cell types from all three germ layers, that is, ectoderm, mesoderm, and endoderm. Multipotent stem cells (such as hematopoietic stem cells) have the ability to develop into more than one specialized cell type, but they cannot make all tissues in the body. Unipotent stem cells, also known as progenitor cells, (such as epithelial stem cells), can only produce one cell type.
A number of sources exist for obtaining stem cells and thus stem cells can also be classified based upon their tissue of origin:
Embryonic stem cells
Fetal stem cells
Umbilical cord stem cells
Adult stem cells
Some believe that adult and fetal stem cells evolved from embryonic stem cells and the few stem cells observed in adult organs are the remnants of original embryonic stem cells that gave up in the race to differentiate into developing organs or remained in cell niches in the organs, which are called upon for repair during tissue injury.
The most common stem cell sources are adult stem cells and embryonic stem (ES) cells.
ES cells are derived from the inner cell mass of the developing embryo during the blastocyst stage. They have the ability to renew themselves indefinitely and are truly pluripotent, that is, they are able to differentiate into all derivatives of the three primary germ layers: ectoderm, endoderm, and mesoderm. Their use, however, is very controversial because of ethical concerns, current regulatory issues regarding their use, and the difficulty of cell acquisition.
In contrast to ES cells, multipotent adult stem cells are characterized by their capacity for self-renewal and differentiation potential limited to tissues of one germ layer. If they have the potential to differentiate into various forms of mesenchymal tissue (i.e., bone, tendon, cartilage, and muscle), they are termed mesenchymal stem cells (MSCs).
A more novel source of stem cells is induced pluripotent stem (iPS) cells, which are initially mature adult stem cells that have undergone in vitro modulation and obtained the characteristics of adult stem cells.
The majority of clinical related stem cells research to date has focused upon adult stem cells rather than embryonic stem cells, as the latter are associated with numerous regulatory and ethical constraints. iPS cells are a relatively new field that has generated a great deal of interest.
MSCs
MSCs are a subset of adult stem cells that may be particularly useful for stem cell-based therapies for three reasons. First, MSCs have been isolated from a variety of mesenchymal tissues, including bone marrow, muscle, circulating blood, blood vessels, and fat, thus making them abundant and readily available [1]. Second, MSCs can differentiate into a wide array of cell types, including osteoblasts, chondrocytes, and adipocytes [2]. This suggests that MSCs may have broader therapeutic applications compared to other adult stem cells. Third, MSCs exert potent paracrine effects, enhancing the ability of injured tissue to repair itself. In fact, animal studies suggest that this may be the predominant mechanism by which MSCs promote tissue repair.
Source of MSC
The principal source for MSCs for RC healing has been autologous bone marrow, for which extraction and culture technique, as well as conditions for propagation have been extensively defined.
The iliac crest is the most common site for MSC harvesting, although a number of other sources have been recently identified. Recently, Mazzocca et al. [3, 4] showed that proximal humerus is a source of MSCs, which can be safely accessible during arthroscopic procedures. Authors characterized the harvested cells as MSCs and induced differentiation in tenocyte-like cells after treatment with insulin. Furthermore, Beizel et al. [5] have shown that arthroscopic aspiration of bone marrow from the proximal humerus is a reproducible technique and yields reliable concentrations of MSCs. These studies demonstrate that MSCs can be harvested avoiding an additional surgical site for aspiration (i.e., iliac crest) or a second operative procedure, making easy future use of MSCs in arthroscopic RC surgery.
MSCs can also be derived from other sources such as accessible adipose tissue, which can also be relatively easily accessible, although these cells have an apparently reduced ability to differentiate compared to bone marrow-derived MSCs [6].
Tendon-derived stem cells (TDSCs) are considered of extreme interest in RC repair enhancement, based on an assumption that these cells would be more appropriate for tendon repair.
Existence of tendon-derived stem cells has been first proved in murine patellar tendons and human hamstrings by Bi et al. [7]. More recent ex vivo studies confirmed TDSCs isolation from animal and human RC tissues. Tsai et al. [8] showed on five patients that cells harvested from the RC tendon could be successfully isolated and differentiated into cells with MSCs characteristics. In 2013, Randelli et al. [9] confirmed the existence of stem cell populations in shoulder tissues; samples from human supraspinatus tendon and human long head of the biceps tendon were collected during arthroscopic RC repairs from 26 patients. Morphology, self-renewal capacity, immunophenotype, gene and protein expression profiles, and differentiation capacity were evaluated, and resulted in characterization of two new types of human stem cells. In the same year, Utsunomiya et al. [10] isolated and characterized MSCs from four shoulder tissues: synovium of glenohumeral joint, subacromial bursa, RC tendon and enthesis at greater tuberosity, obtained from 19 patients undergoing arthroscopic RC repair, suggesting that subacromial bursa is a good candidate for the source of MSCs in RC tears.
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