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Review
. 2013 Jul 1;65(3):1091-133.
doi: 10.1124/pr.112.007393. Print 2013 Jul.

The pharmacology of regenerative medicine

George J Christ  1 , Justin M Saul, Mark E Furth, Karl-Erik Andersson
Affiliations
Review

The pharmacology of regenerative medicine

George J Christ et al. Pharmacol Rev. .

Abstract

Regenerative medicine is a rapidly evolving multidisciplinary, translational research enterprise whose explicit purpose is to advance technologies for the repair and replacement of damaged cells, tissues, and organs. Scientific progress in the field has been steady and expectations for its robust clinical application continue to rise. The major thesis of this review is that the pharmacological sciences will contribute critically to the accelerated translational progress and clinical utility of regenerative medicine technologies. In 2007, we coined the phrase "regenerative pharmacology" to describe the enormous possibilities that could occur at the interface between pharmacology, regenerative medicine, and tissue engineering. The operational definition of regenerative pharmacology is "the application of pharmacological sciences to accelerate, optimize, and characterize (either in vitro or in vivo) the development, maturation, and function of bioengineered and regenerating tissues." As such, regenerative pharmacology seeks to cure disease through restoration of tissue/organ function. This strategy is distinct from standard pharmacotherapy, which is often limited to the amelioration of symptoms. Our goal here is to get pharmacologists more involved in this field of research by exposing them to the tools, opportunities, challenges, and interdisciplinary expertise that will be required to ensure awareness and galvanize involvement. To this end, we illustrate ways in which the pharmacological sciences can drive future innovations in regenerative medicine and tissue engineering and thus help to revolutionize the discovery of curative therapeutics. Hopefully, the broad foundational knowledge provided herein will spark sustained conversations among experts in diverse fields of scientific research to the benefit of all.

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Figures

Fig. 1.
Fig. 1.
Central role of regenerative pharmacology in the development of regenerative medicine technologies and curative therapies. The schematic depicts regenerative pharmacology at the intersection of the classic scientific disciplines traditionally associated with regenerative medicine. Knowledge of biologic system operation (i.e., physiology) leads naturally to system modulation (i.e., pharmacology). This connection underpins traditional small molecule drug therapy, which seeks primarily to ameliorate pathologic symptoms arising from aging and disease. Regenerative pharmacology encompasses a distinct paradigm in that novel technologies arise from contributions to the traditional physiology-pharmacology axis provided by 1) biomedical engineering and 2) an understanding of normal cell and developmental biology and molecular genetics. The synergistic interaction of these disciplines enables the creation of novel technologies to enhance regeneration in vivo or to enable de novo tissue and organ engineering (production of “biological substitutes”) in vitro. The central goal of regenerative pharmacology is to develop potentially curative therapeutics. In this endeavor engineered biologic constructs may serve several purposes. First, they provide tools to determine the etiology of degenerative tissue and organ dysfunction and to identify novel therapeutics. The ability to produce individualized constructs, enabled by induced pluripotent stem cells, will move this approach into the realm of personalized medicine. Advances in miniaturization and the adaptation of engineered biologic systems created by regenerative medicine technologies to high-throughput platforms (i.e., “organs on a chip”) also may usher in a new age in drug development. Finally, the engineered biologic substitutes themselves may serve as therapeutics, capable of reconstituting normal tissue and organ functions when implanted into patients.
Fig. 2.
Fig. 2.
Regenerative medicine and tissue engineering approaches to functional tissue restoration, illustrated for striated muscle. Stem or progenitor cells from an appropriate source, in this case a skeletal muscle biopsy, are expanded in culture to provide the requisite starting cells of correct phenotype for the target tissue or organ of interest. Cells may then be injected systemically or applied directly to the site of injury (i.e., cell therapy). Alternatively, the cells may be combined with a scaffold, either naturally derived or synthetic, to yield a tissue engineered construct. Maturation and conditioning of the construct may be achieved by incubation in a bioreactor prior to implantation in the body. For example, a period of exposure to unidirectional stretch improves functionality of skeletal muscle constructs (Moon et al., 2008; Machingal et al., 2011; Corona et al., 2012). As described in the text, functionalized biomaterials may also be directly implanted for tissue or organ restoration.
Fig. 3.
Fig. 3.
Regenerative pharmacology and the disease process. Schematic diagram shows the initiation, development, and progression of tissue and organ dysfunction, leading ultimately to end organ failure. The potential utility of regenerative pharmacology approaches to the maintenance of normal tissue and organ function or the prophylaxis of continued decline is noted. However, the long-term goal is to develop curative pharmacological approaches that address the entire spectrum of tissue and organ function and dysfunction, so that regardless of the particular circumstance, a potentially curative therapy can be developed and applied. As described in detail in the text, regenerative pharmacology represents a significant departure from more traditional approaches that have necessarily focused on palliation and symptomatic relief of pathologic alterations in tissue and organ function.
Fig. 4.
Fig. 4.
Application of pharmacology to bladder regeneration. (A) Representative illustration of the bladder. (B) Representative concentration-response curve data (CRC) for carbachol (CCh)-induced steady-state contractions of isolated bladder strips obtained from regenerating rat bladders at 2, 4, and 8 weeks post-STC (subtotal cystectomy; modified from Burmeister et al., 2010; see for more details). In short, carbachol dose–response curves are from both control animals and at 2, 4, and 8 weeks post-STC. Responses have been normalized to strip weight. Total area under the curve values were 312.8 for controls, 54.65 at 2 weeks, 61.86 at 4 weeks, and 119.7 at 8 weeks post-STC. Maximal steady-state (Emax) values for all STC animals are significantly lower than control tissue (P < 0.001). Emax values at 8 weeks post-STC are significantly higher than 2 and 4 week time points (P < 0.05). As illustrated, the data reveal a time-dependent increase in the magnitude of carbachol-induced contractile response. Note that although the contractile response never fully recovered from the initial injury, the animals were continent (i.e., the bladder emptied normally). Such observations highlight the importance of pharmacology analyses in general and, in this instance, signal transduction mechanisms in particular, in the evaluation of regeneration. Understanding the mechanisms and characteristics of functional recovery will be a key to designing improved therapeutics for bladder and organ regeneration in the future. (C) Colocalization in cells of incorporated BrdU (bromodeoxyuridine), indicative of proliferation, and specific markers for smooth muscle (SMA, smooth muscle actin) in the muscularis propria (MP) of the regenerating bladder of a female rat [the panel was reproduced from Peyton et al. (2012); additional details can be found in the manuscript as well]. Confocal z-stack reconstruction imaging was performed at 600× magnification, where offset pictures are digitally zoomed. The images were obtained from sections 7 days post-STC and reflect the early proliferative response of the rat bladder. BrdU-SMA colabeling was observed within the MP (C-1), but was relatively rare. BrdU-labeled cells within the MP were more commonly observed between smooth muscle cells as well as smooth muscle bundles (C-2).
Fig. 5.
Fig. 5.
Methods to generate functionalized biomaterials for regenerative medicine. Micro- and nanoparticles for cell and drug delivery (center): several micro- and nanoparticle systems are highlighted schematically. (A) Nanoparticles used for imaging modalities include quantum dots (fluorescence) and iron oxide nanoparticles (magnetic resonance imaging). Nanoparticles with hollow centers are can also be loaded with iodine or other image contrast agents. A schematic of the structure of a quantum dot nanoparticle is shown. (B) In addition to contrast agents, small molecule drugs, nucleic acids, peptides, and protein drugs can be loaded into a variety of self-assembling nanoparticle systems that typically range from 10 to 200 nm. Schematics of DNA-polymer complexes, liposomes, and micelles are shown. (C) These nanoparticles can be surface modified with polyethylene glycol (left) to improve pharmacokinetics or can be modified with targeting motifs to improve cellular uptake (right). (D) Larger microscale constructs can also be formed from natural and synthetic polymers for release of therapeutic agents (right) or the delivery of cells (left) to provide cell-based delivery of, for example, insulin in the treatment of diabetes (Opara et al., 2010). Injectable delivery materials (left): the delivery systems described in the center panel have multiple applications to regenerative medicine when delivered either systemically or locally. (E) Shown is the in vivo tracking of implanted scaffolds containing cells loaded with ultrasmall superparamagnetic iron oxide nanoparticles (Reprinted with permission from Harrington et al., 2011). (F) The use of cationic liposomes to deliver DNA encoding for IGF-1 (and Lac-Z for imaging purposes) is shown at left (Reproduced with permission of BENTHAM SCIENCE PUBLISHERS LTD; Jeschke MG, Herndon DN, Baer W, Barrow RE, and Jauch KW (2001) Possibilities of non-viral gene transfer to improve cutaneous wound healing. Curr Gene Ther 1:267–278), whereas the delivery and protection of Wnt proteins for control of hair follicle stem cells to promote dermal thickening and follicle neogenesis in mice is shown at right (Morrell et al., 2008). (G) The ability to not only localize drugs but have the release of their payload triggered by internal [e.g., pH, temperature change, enzymes) or external (temperature, ultrasound, or as shown, light sources (Reprinted with permission from Azagarsamy MA, Alge DL, Radhakrishnan SJ, Tibbitt MW, and Anseth KS (2012) Photocontrolled nanoparticles for on-demand release of proteins. Biomacromolecules 13:2219–2224. Copyright © 2012, American Chemical Society)]. (H) Incorporation of antigens into microparticles or nanoparticles for improved vaccine delivery is shown at left (Reprinted with permission from Demento SL, Cui W, Criscione JM, Stern E, Tulipan J, Kaech SM, and Fahmy TM (2012) Role of sustained antigen release from nanoparticle vaccines in shaping the T cell memory phenotype. Biomaterials 33:4957–4964) while the use of biomaterial implants is aiding in elucidating and ultimately minimizing inflammatory responses to implanted materials (Reprinted with permission from Norton LW, Park J, and Babensee JE (2010) Biomaterial adjuvant effect is attenuated by anti-inflammatory drug delivery or material selection. J Control Release 146:341–348). Implantable delivery materials (right), delivery systems shown in the center panel may or may not be part of implantable biomaterial scaffolds as well. (I) One example of this achieving spatiotemporal control over multiple growth factors in which one factor is released rapidly from the scaffold material (e.g., VEGF) and a second growth factor (e.g., platelet-derived growth factor) is released at a slower rate from embedded microparticles to promote angiogenesis or support other aspects of tissue formation (Reprinted with permission from Chen RR, Silva EA, Yuen WW, and Mooney DJ (2007) Spatio-temporal VEGF and PDGF delivery patterns blood vessel formation and maturation. Pharm Res 24:258–264). (J) Materials that contain specific topography or pore architecture to simulate native tissue in an increasingly important concept in biomaterial design. As shown, conduits to promote nerve regeneration are advantageous, and the delivery of nerve growth factor from microparticles or the incorporation of extracellular matrix cues such as fibronectin supports these processes (Reprinted with permission from De Laporte L, Huang A, Ducommun MM, Zelivyanska ML, Aviles MO, Adler AF, and Shea LD (2010) Patterned transgene expression in multiple-channel bridges after spinal cord injury. Acta Biomater 6:2889–2897). (K) Methods to incorporate microparticles or nanoparticles into biomaterial scaffolds include incorporation into the matrix of the scaffold (Reprinted with permission from Lee M, Chen TT, Iruela-Arispe ML, Wu BM, and Dunn JC (2007) Modulation of protein delivery from modular polymer scaffolds. Biomaterials 28:1862–1870) or coating onto the scaffold’s pores (Reprinted with permission from Saul JM, Linnes MP, Ratner BD, Giachelli CM, and Pun SH (2007) Delivery of non-viral gene carriers from sphere-templated fibrin scaffolds for sustained transgene expression. Biomaterials 28:4705–4716). (L) Another materials-based approach important to the delivery of therapeutics related to regenerative medicine are microneedle patches that overcome diffusion barriers in the skin to allow more efficient, long-term delivery of therapeutics (Reprinted with permission from Davis SP, Martanto W, Allen MG, and Prausnitz MR (2005) Hollow metal microneedles for insulin delivery to diabetic rats. IEEE Trans Biomed Eng 52:909–915).
Fig. 6.
Fig. 6.
Methods to fabricate biomaterial scaffolds for regenerative medicine applications. There are many approaches to fabricating materials. These approaches range from inexpensive and relatively simple to expensive and quite complex. Several commonly used techniques are shown in this schematic. (A) Solvent evaporation/particulate leaching. A particulate (e.g., sodium chloride) that is insoluble in a particular solvent (e.g., chloroform) is cast with a polymer (e.g., PLGA) in solvent. After the solvent is evaporated, the material can be placed into an alternative solvent in which the particulate is soluble but the polymer is not to form the pores. (B) Sintering—particulate leaching that allows formation of interconnected pores of well-defined architecture. In this approach, leachable polymers are packed together and heated (to above their glass transition temperature) to allow partial fusion of the beads and provide a template. After cooling, a second polymer is cast around the sintered bead template to back-fill the empty regions. The polymer used to fabricate the bead template must be selectively soluble in a solvent. As described above, the bead template is then selectively dissolved in an appropriate solvent to yield a highly porous scaffold with interconnected pores (Fukano et al., 2010; Underwood et al., 2011). (C) Phase separation to introduce porosity (Nam and Park, 1999). This approach involves dissolution of a polymer into a solvent. The temperature is raised to one such that the polymer is fully solubilized. By cooling, the solution can phase separate depending on the concentrations of the solvent and the polymer. This phase separation can achieve solvent-rich regions or polymer-rich regions. Removal of the solvent (e.g., by evaporation) can achieve desirable pore architecture within scaffolds. These can be liquid-liquid phase separations, but it is also possible to introduce gaseous materials to achieve “gas foaming” of the desired pore architecture of the material (Riddle and Mooney, 2004). (D) Electrospinning— polymer dissolved in solvent is ejected through a small orifice (typically a needle). An electrical drop is applied between the orifice and collection device and fine nano-fibers are produced. It is also possible to incorporate nano or microparticles into these electrospun scaffolds (Guo et al., 2012). (E) Microfabrication techniques to introduce very high resolution into materials. Typically, such approaches are not used to produce large three-dimensional scaffolds for implantation. However, the techniques allow for very high levels of control over drug delivery or surface topography, allowing investigation of these effects at the individual cell level. (F) Three-dimensional printing/solid free-form fabrication techniques. These methods achieve high levels of dimensional precision for material fabrication at scale that is suitable for implantable scaffold materials. A polymer (in solvent or melt form) is ejected through a small orifice with high precision on a stage with x-y control. A single “layer” is printed and is akin to printing on a piece of paper with a laser printer. By controlling x, y, and z direction resolution, it is possible to fabricate scaffolds with very precise architecture.
Fig. 7.
Fig. 7.
Methods to tailor polymeric materials for regenerative medicine applications. Schematic highlights important design parameters for biomaterial scaffold fabrication. (Ai) Proteolytic sequences may be natively inherent (e.g., in natural materials) or engineered into synthetic materials; (Aii) Hydrolytically cleavable sequences may also be a part of the polymer backbone. Synthetic-natural polymer hybrids may allow beneficial aspects of both classes of materials (Xu et al., 2012b); (Aiii) Natural polymers may contain peptidic sequences that promote cell attachment and proliferation through their inherent cell-binding motifs. These amino acid sequences include RGD (e.g., collagen), YIGSR (e.g., laminin), and LDV (e.g., keratin). These sequences may also be grafted into synthetic materials or natural materials that do not contain the sequences inherently (Connelly et al., 2011; Rafat et al., 2012; Sapir et al., 2011). (Bi) Internal bonds that are susceptible to cleavage through internal or external stimuli such as heat, pH, ultrasound, or light (Balmayor et al., 2008; Narayanan et al., 2012; Nelson et al., 2012) allow control over rates of degradation; (Bii) Nano- or microparticles may be also be incorporated into the scaffold (Biondi et al., 2009) and may slowly release their contents (typical for microparticles) or may themselves be released from the material (e.g., nanoparticles). A last important consideration in the material’s degradation is the fashion by which it degrades. These include bulk degradation (Biii) or surface erosion (Biv).
Fig. 8.
Fig. 8.
Regenerative pharmacology approaches to Parkinson’s disease. Functional analysis of preclinical cell therapy approach to one PD endpoint, namely, bladder dysfunction or overactivity. Top left and right panels show immunofluorescence (red) for superoxide dismutase-2 (SOD-2; A–C, left) and interleukin-6 (IL-6; A–C, right), respectively, in rat brain cells surrounding and in close contact to amniotic fluid derived stem cells (AFS) or BM-MSC (bone marrow-mesenchymal stem cell; both stem cell populations were green fluorescent protein labeled and green) injected into a unilateral nigrostriatal lesion created 2 weeks earlier by stereotactically injecting 8 μg of 6-OHDA into the right median forebrain bundle (MFB; see Soler et al., 2012 for details). The bottom panel shows representative examples of the corresponding cystometric parameter estimates obtained 14 days after sham-injection or injection of AFS cells or BM-MSC, compared with urodynamic responses observed on a healthy control animal; all data are expressed as the mean ± S.E.M. parameters in sham-treated, AFS, BM-MSC, and healthy control groups during follow up (H1, H2). Red bars represent improvement in AFS-injected versus sham-treated rats. Green bars represent improvement in BM-MSC-injected versus sham-treated rats. Of note, the immunofluorescence was no longer detectable 14 days after AFS injection, while the observed recovery was gone by 28 days post-AFS injection. These data highlight two important points. First, and not surprisingly, human stem cell survival in vivo is short lived (<28 days). Second, nonetheless, they can impart significant pharmacological effects and corresponding functional improvement. That is, human AFS cells can temporarily ameliorate bladder dysfunction in a rodent model of Parkinson’s disease. Panels were reproduced from Soler R, Fullhase C, Hanson A, Campeau L, Santos C, and Andersson KE (2012) J Urol; 2012 Apr;187(4):1491–1497.
Fig. 9.
Fig. 9.
Five strategies by which regenerative pharmacology can affect biology of stem and progenitor cells. Red arrows indicate steps at which a pharmacological agent may be applied. (A) Expansion of lineage-restricted stem or progenitor cells (depicted in cartoon form as blue cells with large nuclei). Exemplified here by isolation of hematopoietic stem cells (HSC, e.g., CD34-positive cells) from human bone marrow and expansion in culture using a cocktail of cytokines/growth factors including angiopoietin-like 5 (AGPTL5) (Drake et al., 2011), prior to infusion into a patient small molecules, such as an aryl hydrocarbon receptor antagonist designated StemRegenin 1 (SR1) (Boitano et al., 2010), likewise can promote HSC expansion in culture. (B) Mobilization of stem cells from an endogenous niche. Exemplified by recruitment of stem cells from tissue niches (blue crescent) to enter the circulation (cylinder depicts a blood vessel) and potentially to undergo expansion prior to further lineage commitment. Plerixafor (Brave et al., 2010) is a small molecule that drives HSC mobilization from bone marrow niches, used in combination with G-CSF. Pleiotrophin (Himburg et al., 2010; Istvanffy et al., 2011) promotes expansion of the HSC pool in vivo. The cells are collected from a donor by apheresis. (C) Differentiation of committed progenitor cells to functional, specialized cells. Exemplified by accelerated maturation of granulocyte progenitors to infection-fighting neutrophils (left) promoted by G-CSF (Frampton et al., 1994) and of erythroid progenitors to red blood cells (right) promoted by erythropoietin (EPO) (Faulds and Sorkin, 1989). (D) Production of specialized cells from pluripotent stem cells (ES or iPS cells) by sequential steps of lineage commitment and terminal differentiation. Pluripotent stem cells are depicted iconically as a cluster with nuclei stained for the pluripotency-associated transcription factor Oct4. Cardiomyocytes (shown iconically by staining for cardiac troponin and other heart-specific proteins) represent a cell type that might be used in tissue engineering and for drug discovery. A key factor in the promotion of commitment to mesodermal and cardiac fates is BMP-4 (Evseenko et al., 2010; Hogan, 1996; Kattman et al., 2011; Murry and Keller, 2008). Small molecule inhibitors of Wnt/beta-catenin signaling, such as IWR-1 (Chen et al., 2009; Willems et al., 2011), drive the generation of cardiomyocytes from human ES cell-derived mesoderm. (E) Production of genetically compatible induced pluripotent stem (iPS) cells from an individual’s own cells. Autologous cells such as skin fibroblasts (shown iconically by staining for F-actin in the cytoskeleton) are reprogrammed to pluripotency by exposure to a set of four transcription factors [e.g., the four identified by the Thomson group—Oct4, Nanog, Sox2, and Lin 28 (Yu et al., 2007)]. The small molecule AMI-5 (Yuan et al., 2011b), an inhibitor of protein arginine methyltransferase (PRMT), enables reprogramming in conjunction with Oct4 alone.
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References

    1. Agholme F, Aspenberg P. (2011) Wnt signaling and orthopedics, an overview. Acta Orthop 82:125–130 - PMC - PubMed
    1. Ananiev G, Williams EC, Li H, Chang Q. (2011) Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model. PLoS ONE 6:e25255. - PMC - PubMed
    1. Andersson KE, Chapple CR, Cardozo L, Cruz F, Hashim H, Michel MC, Tannenbaum C, Wein AJ. (2009) Pharmacological treatment of overactive bladder: report from the International Consultation on Incontinence. Curr Opin Urol 19:380–394 - PubMed
    1. Andersson KE, Christ GJ. (2007) Regenerative pharmacology: the future is now. Mol Interv 7:79–86 - PubMed
    1. Aron L, Klein R. (2011) Repairing the parkinsonian brain with neurotrophic factors. Trends Neurosci 34:88–100 - PubMed

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