Delivery of Mesenchymal Stem Cells from Gelatin–Alginate Hydrogels to Stomach Lumen for Treatment of Gastroparesis

Gastroparesis (GP) is associated with depletion of interstitial cells of Cajal (ICCs) and enteric neurons, which leads to pyloric dysfunction followed by severe nausea, vomiting and delayed gastric emptying. Regenerating these fundamental structures with mesenchymal stem cell (MSC) therapy would be helpful to restore gastric function in GP. MSCs have been successfully used in animal models of other gastrointestinal (GI) diseases, including colitis. However, no study has been performed with these cells on GP animals. In this study, we explored whether mouse MSCs can be delivered from a hydrogel scaffold to the luminal surfaces of mice stomach explants. Mouse MSCs were seeded atop alginate–gelatin, coated with poly-l-lysine. These cell–gel constructs were placed atop stomach explants facing the luminal side. MSCs grew uniformly all across the gel surface within 48 h. When placed atop the lumen of the stomach, MSCs migrated from the gels to the tissues, as confirmed by positive staining with vimentin and N-cadherin. Thus, the feasibility of transplanting a cell–gel construct to deliver stem cells in the stomach wall was successfully shown in a mice stomach explant model, thereby making a significant advance towards envisioning the transplantation of an entire tissue-engineered ‘gastric patch’ or ‘microgels’ with cells and growth factors.

[1]  B. Joddar,et al.  A Contact-Based Method for Differentiation of Human Mesenchymal Stem Cells into an Endothelial Cell-Phenotype , 2018, Cell Biochemistry and Biophysics.

[2]  B. Joddar,et al.  A Bioactive Hydrogel and 3D Printed Polycaprolactone System for Bone Tissue Engineering , 2017, Gels.

[3]  G. Besner,et al.  Heparin-binding EGF-like growth factor promotes neuronal nitric oxide synthase expression and protects the enteric nervous system after necrotizing enterocolitis , 2017, Pediatric Research.

[4]  Joachim P Spatz,et al.  Stem cell migration and mechanotransduction on linear stiffness gradient hydrogels , 2017, Proceedings of the National Academy of Sciences.

[5]  P. Sansonetti,et al.  CD34+ mesenchymal cells are a major component of the intestinal stem cells niche at homeostasis and after injury , 2017, Proceedings of the National Academy of Sciences.

[6]  Philippe Aubert,et al.  Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system , 2016, Nature Medicine.

[7]  A. Hsieh,et al.  Deformability of Human Mesenchymal Stem Cells Is Dependent on Vimentin Intermediate Filaments , 2017, Annals of Biomedical Engineering.

[8]  P. Thomsen,et al.  Inflammatory cell response to ultra-thin amorphous and crystalline hydroxyapatite surfaces , 2016, Journal of Materials Science: Materials in Medicine.

[9]  B. Joddar,et al.  Development of functionalized multi-walled carbon-nanotube-based alginate hydrogels for enabling biomimetic technologies , 2016, Scientific Reports.

[10]  M. Medvedovic,et al.  The Development of Spasmolytic Polypeptide/TFF2-Expressing Metaplasia (SPEM) During Gastric Repair Is Absent in the Aged Stomach , 2016, Cellular and molecular gastroenterology and hepatology.

[11]  F. Bendtsen,et al.  Validation and Optimization of an Ex Vivo Assay of Intestinal Mucosal Biopsies in Crohn’s Disease: Reflects Inflammation and Drug Effects , 2016, PloS one.

[12]  R. Misra,et al.  The functional response of alginate-gelatin-nanocrystalline cellulose injectable hydrogels toward delivery of cells and bioactive molecules. , 2016, Acta biomaterialia.

[13]  Wei Sun,et al.  Bioprinting three-dimensional cell-laden tissue constructs with controllable degradation , 2016, Scientific Reports.

[14]  S. Kundu,et al.  Fabrication of cationized gelatin nanofibers by electrospinning for tissue regeneration , 2015 .

[15]  Lin Zhao,et al.  Synthesis of Quercetin Loaded Nanoparticles Based on Alginate for Pb(II) Adsorption in Aqueous Solution , 2015, Nanoscale Research Letters.

[16]  R. McCallum,et al.  Is Interstitial Cells of Cajal–opathy Present in Gastroparesis? , 2015, Journal of neurogastroenterology and motility.

[17]  R. Rajesh,et al.  Development of a new carbon nanotube–alginate–hydroxyapatite tricomponent composite scaffold for application in bone tissue engineering , 2015, International journal of nanomedicine.

[18]  David J. Mooney,et al.  Matrix Elasticity of Void-Forming Hydrogels Controls Transplanted Stem Cell-Mediated Bone Formation , 2015, Nature materials.

[19]  Angelo S. Mao,et al.  Microfluidic Generation of Monodisperse, Structurally Homogeneous Alginate Microgels for Cell Encapsulation and 3D Cell Culture , 2015, Advanced healthcare materials.

[20]  R. McCallum,et al.  Motility: Is 'ICC-opathy' present in gastroparesis-like syndrome? , 2015, Nature Reviews Gastroenterology &Hepatology.

[21]  Yuezhi Cui,et al.  Anti-degradation gelatin films crosslinked by active ester based on cellulose , 2015 .

[22]  T. Smyrk,et al.  Stem cells for murine interstitial cells of cajal suppress cellular immunity and colitis via prostaglandin E2 secretion. , 2015, Gastroenterology.

[23]  L. Suggs,et al.  Dynamic phototuning of 3D hydrogel stiffness , 2015, Proceedings of the National Academy of Sciences.

[24]  Masaaki Oka,et al.  Influence of mesenchymal stem cells on stomach tissue engineering using small intestinal submucosa , 2013, Journal of tissue engineering and regenerative medicine.

[25]  Liuli,et al.  Thermoswitching Microgel Carriers Improve Neuronal Cell Growth and Cell Release for Cell Transplantation , 2015 .

[26]  L. Chu,et al.  Thermoswitching microgel carriers improve neuronal cell growth and cell release for cell transplantation. , 2015, Tissue engineering. Part C, Methods.

[27]  Jia Liu,et al.  Cell-based Therapy for Acute Organ Injury: Preclinical Evidence and Ongoing Clinical Trials Using Mesenchymal Stem Cells , 2014, Anesthesiology.

[28]  Xueqin Zhang,et al.  Crosslinked polyelectrolyte complex fiber membrane based on chitosan–sodium alginate by freeze-drying , 2014 .

[29]  Rinti Banerjee,et al.  Self-crosslinked oxidized alginate/gelatin hydrogel as injectable, adhesive biomimetic scaffolds for cartilage regeneration. , 2014, Acta biomaterialia.

[30]  Kyung-Chul Choi,et al.  Role of the epithelial–mesenchymal transition and its effects on embryonic stem cells , 2014, Experimental & Molecular Medicine.

[31]  Xinfeng Hou,et al.  MiR‐335‐5p Promotes Chondrogenesis in Mouse Mesenchymal Stem Cells and Is Regulated Through Two Positive Feedback Loops , 2014, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[32]  K. Park Is This the Era of Interstitial Cells of Cajal Transplantation? , 2014, Journal of neurogastroenterology and motility.

[33]  Xu Huang,et al.  Gastric nNOS reduction accompanied by natriuretic peptides signaling pathway upregulation in diabetic mice. , 2014, World journal of gastroenterology.

[34]  A. Boccaccini,et al.  Fabrication of alginate-gelatin crosslinked hydrogel microcapsules and evaluation of the microstructure and physico-chemical properties. , 2014, Journal of materials chemistry. B.

[35]  A. Filby,et al.  A method for evaluating the use of fluorescent dyes to track proliferation in cell lines by dye dilution , 2013, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[36]  M. Shin,et al.  Tissue engineering of the stomach. , 2013, The Journal of surgical research.

[37]  S. Ward,et al.  Establishment of pacemaker activity in tissues allotransplanted with interstitial cells of Cajal , 2013, Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society.

[38]  Huaping Tan,et al.  Alginate-Based Biomaterials for Regenerative Medicine Applications , 2013, Materials.

[39]  B. Bhushan,et al.  Heparin-binding epidermal growth factor-like growth factor and mesenchymal stem cells act synergistically to prevent experimental necrotizing enterocolitis. , 2012, Journal of the American College of Surgeons.

[40]  Lei Cai,et al.  Optimal poly(L-lysine) grafting density in hydrogels for promoting neural progenitor cell functions. , 2012, Biomacromolecules.

[41]  F. Sala,et al.  Murine tissue-engineered stomach demonstrates epithelial differentiation. , 2011, The Journal of surgical research.

[42]  H. Taniguchi,et al.  Evidence for Mesenchymal−Epithelial Transition Associated with Mouse Hepatic Stem Cell Differentiation , 2011, PloS one.

[43]  Yan He,et al.  Is gastrointestinal dysfunction induced by gastric cancer peritoneal metastasis relevant to impairment of interstitial cells of Cajal? , 2011, Clinical & Experimental Metastasis.

[44]  Y. Song,et al.  Regional Distribution of Interstitial Cells of Cajal (ICC) in Human Stomach. , 2010, The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology.

[45]  T. Nagayasu,et al.  Development of a new tissue-engineered sheet for reconstruction of the stomach. , 2009, Artificial organs.

[46]  Ravi S Kane,et al.  The influence of hydrogel modulus on the proliferation and differentiation of encapsulated neural stem cells. , 2009, Biomaterials.

[47]  Daniel B. Jones,et al.  In situ measurement and modeling of biomechanical response of human cadaveric soft tissues for physics-based surgical simulation , 2009, Surgical Endoscopy.

[48]  A. Lorincz,et al.  Progenitors of interstitial cells of cajal in the postnatal murine stomach. , 2008, Gastroenterology.

[49]  Ali Khademhosseini,et al.  Microengineered hydrogels for tissue engineering. , 2007, Biomaterials.

[50]  J. Huizinga,et al.  Interstitial cells of Cajal in health and disease. Part I: Normal ICC structure and function with associated motility disorders , 2007, Histopathology.

[51]  Catherine M. Verfaillie,et al.  Pluripotency of mesenchymal stem cells derived from adult marrow , 2007, Nature.

[52]  J. Donnez,et al.  Clinical evaluation of a viscoelastic gel for reduction of adhesions following gynaecological surgery by laparoscopy in Europe. , 2005, Human reproduction.

[53]  S. Ward,et al.  Intestinal surgical resection disrupts electrical rhythmicity, neural responses, and interstitial cell networks. , 2004, Gastroenterology.

[54]  Hidetaka Mochizuki,et al.  Initial Assessment of A Tissue Engineered Stomach Derived From Syngeneic Donors in a Rat Model , 2004, ASAIO journal.

[55]  Moustapha Hassan,et al.  Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells , 2004, The Lancet.

[56]  N. Wright,et al.  The gastrointestinal stem cell , 2004, Cell proliferation.

[57]  Tatsuo Nakamura,et al.  Functional analysis of the tissue-engineered stomach wall. , 2002, Artificial organs.

[58]  N. Wright,et al.  Gastrointestinal stem cells , 2002, The Journal of pathology.

[59]  D. Orlic Stem cell repair in ischemic heart disease: An experimental model , 2002, International journal of hematology.

[60]  J. Albores‐Saavedra,et al.  Stromal tumor of the gallbladder with phenotype of interstitial cells of Cajal: a previously unrecognized neoplasm. , 2000, The American journal of surgical pathology.

[61]  K. Chorneyko,et al.  Gastrointestinal stromal tumors may originate from a subset of CD34-positive interstitial cells of Cajal. , 2000, The American journal of pathology.

[62]  J. Feijen,et al.  Cross-linking and characterisation of gelatin matrices for biomedical applications , 2000, Journal of biomaterials science. Polymer edition.

[63]  J. Feijen,et al.  Characterization of the Network Structure of Carbodiimide Cross-Linked Gelatin Gels , 1999 .

[64]  S. Ward,et al.  Development of c-Kit-positive cells and the onset of electrical rhythmicity in murine small intestine. , 1997, Gastroenterology.

[65]  A. Boskey,et al.  Osteopontin-hydroxyapatite interactions in vitro: inhibition of hydroxyapatite formation and growth in a gelatin-gel. , 1993, Bone and mineral.