Fibroblasts As a Practical Alternative to Mesenchymal Stem Cells Thomas E
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Ichim et al. J Transl Med (2018) 16:212 https://doi.org/10.1186/s12967-018-1536-1 Journal of Translational Medicine REVIEW Open Access Fibroblasts as a practical alternative to mesenchymal stem cells Thomas E. Ichim1*†, Pete O’Heeron1† and Santosh Kesari2 Abstract Mesenchymal stem cell (MSC) therapy ofers great potential for treatment of disease through the multifunctional and responsive ability of these cells. In numerous contexts, MSC have been shown to reduce infammation, modulate immune responses, and provide trophic factor support for regeneration. While the most commonly used MSC source, the bone marrow provides relatively little starting material for cellular expansion, and requires invasive extraction means, fbroblasts are easily harvested in large numbers from various biological wastes. Additionally, in vitro expan- sion of fbroblasts is signifcantly easier given the robustness of these cells in tissue culture and shorter doubling time compared to typical MSC. In this paper we put forward the concept that in some cases, fbroblasts may be utilized as a more practical, and potentially more efective cell therapy than mesenchymal stem cells. Anti-infammatory, immune modulatory, and regenerative properties of fbroblasts will be discussed in the context of regenerative medicine. Keywords: Stem cell therapy, Regenerative medicine, Disc degenerative disease, Fibroblasts, Mesenchymal stem cells Introduction to other bone marrow mononuclear cells, specifcally, Friedenstein and colleagues were the frst to describe 1:10,000 to 1:100,000 [14]. Te physiological role of MSC mesenchymal stem cells (MSC) as adherent cells derived still remains to be fully elucidated, with one hypoth- from bone marrow that were capable of forming colonies esis being that bone marrow MSC act as precursors for and comprising the radioresistant fraction of cells associ- stromal cells that make up the hematopoietic stem cell ated with hematopoiesis [1, 2]. Tere cells are currently microenvironment [15–17]. defned as adherent, non-hematopoietic cells expressing Te frst clinical use of MSC was reported in a 1995 markers such as CD90, CD105, and CD73, while lacking paper, in which Lazarus et al. reported the use of autolo- expression of CD14, CD34, and CD45, and being able to gous, in vitro expanded, “mesenchymal progenitor cells” diferentiate into adipocytes, chondrocytes, and osteo- to treat 15 patients sufering from hematological malig- cytes in vitro after treatment with diferentiation induc- nancies in remission. Te authors demonstrated that a ing agents [3]. Although early studies in the late 1960s 10 cc bone marrow sample was capable of 16,000-fold initially identifed MSC in the bone marrow [4], more growth over a 4–7 week in vitro culture. Cell adminis- recent studies have reported these cells can be purifed tration was performed in total doses ranging from 1 to 6 from various tissues such as adipose [5], heart [6], Whar- 50 × 10 cells and was not causative of treatment associ- ton’s Jelly [7], dental pulp [8], peripheral blood [9], cord ated adverse efects [18]. In a subsequent study from the blood [10], and more recently menstrual blood [11–13]. same group, the use of MSC to accelerate hematopoi- Studies in the bone marrow showed that although MSC etic reconstitution was performed in 28 breast cancer are the primary cell type that overgrows in in vitro cul- patients who received high dose chemotherapy. MSC at 6 tures, in vivo MSC are found at a low ratio compared concentrations of 1.0–2.2 × 10 /kg, were administered intravenously with no treatment associated adverse *Correspondence: [email protected] efects. Te authors noted that leukocytic and throm- †Thomas E. Ichim and Pete O’Heeron have contributed equally to the bocytic reconstitution occurred at an accelerated rate as publication of this paper compared to historical controls [19]. It is important to 1 SpinalCyte LLC, Houston, TX, USA Full list of author information is available at the end of the article note that these initial clinical experiences with MSC were © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ichim et al. J Transl Med (2018) 16:212 Page 2 of 9 in patients with oncological indications and no overt During wound healing, scar tissue is formed by fbro- acceleration of cancer progression was noted. Tis has blast over proliferation. In embryos, and in some types of been a concern given that MSC are known to be angio- amphibians, scarless healing occurs after injury, by pro- genic [20–25], produce mitogenic/antiapoptotic factors cesses which are currently under intense investigation [26–32], and exert an immune suppressive efect [33–40]. [62, 63]. With aging, many kinds of tissues and organs Besides feasibility, these studies were important because undergo fbrosis gradually, such as fbrosis of skin, lung, they established the technique for ex vivo expansion and liver, kidney and heart. Te process of scar tissue for- re-administration. mation is caused by hyperproliferation of fbroblasts, as Te demonstration of clinical feasibility, combined with well as these cells producing abnormally large amounts animal models supporting therapeutic efcacy of MSC of extracellular matrix and collagens during proliferation in non-hematopoietic indications [41–48], gave rise to a and thereby replacing normal organ structure (paren- series of clinical trials with MSC in a wide range of thera- chyma), leading to functional impairment and scar for- peutic areas ranging from major diseases such as stroke mation, which may further trigger persistent fbrosis. [49–52], heart failure [53, 54], COPD [55], and liver fail- Te original thinking on fbroblasts was that these cells ure [56], as well as rare diseases such as osteogenesis possess similar characteristics regardless of their source imperfecta [57], Hurler syndrome [58], and Duchenne of origin, a notion that is no longer believed to be entirely Muscular Dystrophy [59]. Te ability to generate large correct [64]. For example, studies have shown that pro- amounts of defned MSC starting with a small clinical tein antigens such as MHC II [65], C1q receptor [66], sample, to administer without need for haplotype match- LR8 [67], and Ty-1 [68], difer in expression based on ing, and excellent safety profle, has resulted in a cur- tissue origin of fbroblasts. Interestingly, not only origin rent 367 clinical trials listed on the international registry of fbroblasts afects markers but also proliferating state. clinicaltrials.gov. While some trials have demonstrated For example, one study showed that CD40 expression efcacy of MSC, little is known about molecular mech- on fbroblasts was elevated on proliferating fbroblasts anisms. Initial studies demonstrated ability of certain but reduced on non-proliferating cells [69]. Other varia- MSC types to diferentiate into functional tissues that is tions in fbroblasts have been detected in various tissues compromised as a result of the underlying pathological. for example, lung fbroblasts are known to possess vari- Although MSC appear to be ideal as a source for devel- able expression of both cell surface marker expression, as opment of cellular therapeutics, there are several draw- well as in their levels of collagen production [70]. Fibro- backs. Firstly, MSC are relatively rare cells in tissue, with blasts derived from periodontal tissue possess diferences bone marrow containing 1:10,000 to 1:100,000 MSC per in extracellular matrix production, glycogen pools, and nucleated cells [14]. In order to generate therapeuti- morphology [71]. cally relevant doses (1–2 million/kg), the MSC need to At present there is a defciency in specifc and repro- undergo massive numbers of cell multiplication in vitro. ducible markers for fbroblasts, which has hampered to Tis increases both the possibility of mutatgenesis, as some extent, our knowledge of in vivo functionality [72, well as loss of activity. Accordingly, tissue sources, such 73]. Currently one of the main means of detecting fbro- as fbroblasts, in which larger numbers of cells may be blasts is quantifcation of vimentin expression. Vimentin, originally extracted, may serve as an attractive alternative is major structural component of the intermediate fla- to MSC. Secondly, fbroblasts typically possess a shorter ments in many cell types, is shown to play an important doubling time than MSC, allowing for less tissue culture role in vital mechanical and biological functions such media use in their expansion, thus reducing cost of pro- as cell contractility, migration, stifness, stifening, and duction. Finally, MSC generation often involves isolation proliferation [74, 75]. One disadvantage of this marker and in vitro growth of the cellular product. In contrast, is that it is also found on endothelial cells of capillaries fbroblasts may be grown without need for isolation of that often locate very close to fbroblasts, additionally, it specifc subtypes of cells. is found on neurons [76]. Another marker of fbroblasts, that is preferentially found on cardiac derived fbroblasts Properties of fbroblasts is the collagen receptor Discoidin Domain Receptor 2 Fibroblasts comprise the main cell type of connective (DDR2 [77]). Unfortunately DDR2 has also been found tissue, possessing a spindle-shaped morphology, whose non-fbroblast cells such as neutrophils [78], dendritic classical function has historically been believed to pro- cells [79, 80], and osteoblasts [81]. Investigators typically duce extracellular matrix responsible for maintaining refer to Ty-1, also known as CD90, as a marker associ- structural integrity of tissue. Fibroblasts also play an ated with fbroblasts.