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Physiologic expansion of human heart-derived cells enhances therapeutic repair of injured myocardium

Mount, Seth, Kanda, Pushpinder, Parent, Sandrine, Khan, Saad, Michie, Connor, Davila, Liliana, Chan, Vincent, Davies, Ross A., Haddad, Haissam, Courtman, David, Stewart, Duncan J., Davis, Darryl R.·2019·Stem Cell Research & Therapy
DOI 10.1186/s13287-019-1418-3PMC PMC6829847
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Abstract

Background: Serum-free xenogen-free defined media and continuous controlled physiological cell culture conditions have been developed for stem cell therapeutics, but the effect of these conditions on the relative potency of the cell product is unknown. As such, we conducted a head-to-head comparison of cell culture conditions on human heart explant-derived cells using established in vitro measures of cell potency and in vivo functional repair. Methods: Heart explant-derived cells cultured from human atrial or ventricular biopsies within a serum-free xenogen-free media and a continuous physiological culture environment were compared to cells cultured under traditional (high serum) cell culture conditions in a standard clean room facility. Results: Transitioning from traditional high serum cell culture conditions to serum-free xenogen-free conditions had no effect on cell culture yields but provided a smaller, more homogenous, cell product with only minor antigenic changes. Culture within continuous physiologic conditions markedly boosted cell proliferation while increasing the expression of stem cell-related antigens and ability of cells to stimulate angiogenesis. Intramyocardial injection of physiologic cultured cells into immunodeficient mice 1 week after coronary ligation translated into improved cardiac function and reduced scar burden which was attributable to increased production of pro-healing cytokines, extracellular vesicles, and microRNAs. Conclusions: Continuous physiological cell culture increased cell growth, paracrine output, and treatment outcomes to provide the greatest functional benefit after experimental myocardial infarction.

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Fig. 1 Study outline. a Schematic contrasting cell culture within a standard clean room environment (STD env) with an isolated facility that continually maintains normal cardiac physiological conditions (37 °C, 80% relative humidity (rh), and 5% oxygen (O2)). b Schematic outlining human atrial and ventricular tissue processing compared throughout the study and key outcomes
Fig. 1 Study outline. a Schematic contrasting cell culture within a standard clean room environment (STD env) with an isolated facility that continually maintains normal cardiac physiological conditions (37 °C, 80% relative humidity (rh), and 5% oxygen (O2)). b Schematic outlining human atrial and ventricular tissue processing compared throughout the study and key outcomesCC BY · PubMed Central
Fig. 2 Effects of serum-free good manufacturing practices (GMP) compatible culture conditions on explant-derived cell (EDC) phenotype. Representative brightfield images of plated cardiac tissue fragments and EDC outgrowth under 20% serum conditions. a 1 day post-plating. b 3 days post-plating. c 7 days post-plating. Representative brightfield images of plated cardiac tissue fragments and EDC outgrowth under serum-free conditions. d 1 day post-plating. e 3 days post-plating. f 7 days post-plating. g Flow cytometry demonstrating that cells cultured in SF STD env conditions were smaller and more homogenous than cells cultured in serum STD env conditions. h Immunohistochemical staining for the cell cycle-associated protein Ki67 in conjunction with DAPI (left panel). Senescence-associated beta-galactosidase+ (β-Gal+) EDCs identified under phase-contrast microscopy by the presence of intracellular hydrolyzed X-galactosidase (right panel). i, j Flow cytometry analysis of phenotypic composition of EDCs. k Effect of cell culture conditions on the ability of EDCs to stimulate human umbilical vein endothelial cells (HUVECs) tubule formation (left panel) or attract circulating angiogenic cells (CACs) across a transwell membrane (right panel; expressed as fold change number of migrated cells compared to basal media containing 100 ng vascular endothelial growth hormone (VEGF; normalization control)). *p ≤ 0.05, **p ≤ 0.01, n = 4 to 5 cell cultures per group. abcg2, ATP-binding cassette sub-family G member 2; cad11, Cadherin-11; DDR2, discoidin domain receptor tyrosine kinase 2; Lin, hematological lineage cocktail; PDGFR, platelet-derived growth factor receptor; SSEA-1, stage-specific embryonic antigen-1
Fig. 2 Effects of serum-free good manufacturing practices (GMP) compatible culture conditions on explant-derived cell (EDC) phenotype. Representative brightfield images of plated cardiac tissue fragments and EDC outgrowth under 20% serum conditions. a 1 day post-plating. b 3 days post-plating. c 7 days post-plating. Representative brightfield images of plated cardiac tissue fragments and EDC outgrowth under serum-free conditions. d 1 day post-plating. e 3 days post-plating. f 7 days post-plating. g Flow cytometry demonstrating that cells cultured in SF STD env conditions were smaller and more homogenous than cells cultured in serum STD env conditions. h Immunohistochemical staining for the cell cycle-associated protein Ki67 in conjunction with DAPI (left panel). Senescence-associated beta-galactosidase+ (β-Gal+) EDCs identified under phase-contrast microscopy by the presence of intracellular hydrolyzed X-galactosidase (right panel). i, j Flow cytometry analysis of phenotypic composition of EDCs. k Effect of cell culture conditions on the ability of EDCs to stimulate human umbilical vein endothelial cells (HUVECs) tubule formation (left panel) or attract circulating angiogenic cells (CACs) across a transwell membrane (right panel; expressed as fold change number of migrated cells compared to basal media containing 100 ng vascular endothelial growth hormone (VEGF; normalization control)). *p ≤ 0.05, **p ≤ 0.01, n = 4 to 5 cell cultures per group. abcg2, ATP-binding cassette sub-family G member 2; cad11, Cadherin-11; DDR2, discoidin domain receptor tyrosine kinase 2; Lin, hematological lineage cocktail; PDGFR, platelet-derived growth factor receptor; SSEA-1, stage-specific embryonic antigen-1CC BY · PubMed Central
Fig. 3 Influence of physiological environment cell culture conditions on explant-derived cell (EDC) culture. a Representative images of plated tissue from two initial cell cultures (UOHI01 and UOHI02) demonstrating progressive spontaneous migration of EDCs from the plated tissue to cover the cultureware over 9 days in culture. b Table outlining the cell yields and viability of the initial three cell cultures demonstrating the impact of reducing the interval between cell culture harvests. c Representative images from the initial cell cultures attempted showing sparse EDC outgrowth after the initial enzymatic harvest and the formation of adherent monolayers that occurred over time. d Experimental schemata, representative images, and experimental outcomes demonstrating the influence of altering cell culture conditions on EDC yields after the first enzymatic digestion. SF, serum free
Fig. 3 Influence of physiological environment cell culture conditions on explant-derived cell (EDC) culture. a Representative images of plated tissue from two initial cell cultures (UOHI01 and UOHI02) demonstrating progressive spontaneous migration of EDCs from the plated tissue to cover the cultureware over 9 days in culture. b Table outlining the cell yields and viability of the initial three cell cultures demonstrating the impact of reducing the interval between cell culture harvests. c Representative images from the initial cell cultures attempted showing sparse EDC outgrowth after the initial enzymatic harvest and the formation of adherent monolayers that occurred over time. d Experimental schemata, representative images, and experimental outcomes demonstrating the influence of altering cell culture conditions on EDC yields after the first enzymatic digestion. SF, serum freeCC BY · PubMed Central
Fig. 4 Influence of culture conditions on heart explant-derived cell (EDC) mediated repair of injured myocardium. a Schemata of the experimental protocol demonstrating echocardiographic-guided intramyocardial injection of 100,000 EDCs into immunodeficient non-obese diabetic severed combined immunodeficient mice 1 week after left coronary artery (LCA) ligation. EDCs cultured using standard serum media in standard cell culture conditions (Serum STD env), serum-free media in STD cell culture conditions (SF STD env), serum-free media-derived EDCs expanded for 1 week in STD cell culture conditions (exSF STD env), and SF media expanded EDCs cultured entirely within continuous physiologic controlled (exSF Phys Env) culture conditions were compared. b Effects of EDC transplant on echocardiographic ejection fraction 3 weeks after cell injection. n = 10 to 13 per group. c EDC engraftment 3 weeks after intramyocardial injection as determined using quantitative polymerase chain reaction analysis for retained human alu sequences (left panel; n = 6 per group) or random field counts of human nuclear antigen+ (HNA+)/4′,6-diamidino-2-phenylindole+ (DAPI+) cells (right panel; n = 8 per group). d Effects of EDC transplant on vessel density (isolectin B4+) within the peri-infarct region. n = 5 per group. e Effects of EDCs on the overall percentage infarcted myocardium (left panel; n = 5 per group) and percentage of viable myocardium within the infarct zone (right panel; n = 6 per group) as determined from Masson’s trichrome staining. *p ≤ 0.05. LCA, left coronary artery; NOD-SCID, non-obese diabetic severe combined immunodeficient; qPCR, quantitative polymerase chain reaction
Fig. 4 Influence of culture conditions on heart explant-derived cell (EDC) mediated repair of injured myocardium. a Schemata of the experimental protocol demonstrating echocardiographic-guided intramyocardial injection of 100,000 EDCs into immunodeficient non-obese diabetic severed combined immunodeficient mice 1 week after left coronary artery (LCA) ligation. EDCs cultured using standard serum media in standard cell culture conditions (Serum STD env), serum-free media in STD cell culture conditions (SF STD env), serum-free media-derived EDCs expanded for 1 week in STD cell culture conditions (exSF STD env), and SF media expanded EDCs cultured entirely within continuous physiologic controlled (exSF Phys Env) culture conditions were compared. b Effects of EDC transplant on echocardiographic ejection fraction 3 weeks after cell injection. n = 10 to 13 per group. c EDC engraftment 3 weeks after intramyocardial injection as determined using quantitative polymerase chain reaction analysis for retained human alu sequences (left panel; n = 6 per group) or random field counts of human nuclear antigen+ (HNA+)/4′,6-diamidino-2-phenylindole+ (DAPI+) cells (right panel; n = 8 per group). d Effects of EDC transplant on vessel density (isolectin B4+) within the peri-infarct region. n = 5 per group. e Effects of EDCs on the overall percentage infarcted myocardium (left panel; n = 5 per group) and percentage of viable myocardium within the infarct zone (right panel; n = 6 per group) as determined from Masson’s trichrome staining. *p ≤ 0.05. LCA, left coronary artery; NOD-SCID, non-obese diabetic severe combined immunodeficient; qPCR, quantitative polymerase chain reactionCC BY · PubMed Central
Fig. 5 Influence of serum free culture conditions on the paracrine signature of explant-derived cells (EDCs). a Select cytokines from an unbiased protein array profiling cytokine content within EDC conditioned media under hypoxic (1% oxygen) basal media conditions. *p < 0.05 vs. media conditioned by EDCs cultured within standard (STD) cell conditions. n=4 per group. b Select cytokines from an unbiased proteome array showing differential expression within media conditioned by STD EDCs and exSF Phys Env EDCs. *p < 0.05 vs. media conditioned by EDCs cultured within standard (STD) cell conditions. n=4 per group. c Effect of cell culture conditions on extracellular vesicle concentration and size. *p < 0.05 vs. all. N=3-4 per group. d Up and downregulated miRNAs in EVs isolated from exSF Phys Env EDCs compared to serum STD EDCs. n=3. FGF basic: Fibroblast growth factor basic; Flt-3: tyrosine kinase 3; GM-CSF: Granulocyte-macrophage colony-stimulating factor; HGF: Hepatocyte growth factor; ICAM: Intercellular adhesion molecule; IGFBP: Insulin-like growth factor binding protein; IL: interleukin; OPG: Osteoprotegerin; PDGF: Platelet-derived growth factor; SDF-1α: stromal cell-derived factor 1 alpha; uPAR: urokinase-type plasminogen activator; VEGF: Vascular endothelial growth hormone
Fig. 5 Influence of serum free culture conditions on the paracrine signature of explant-derived cells (EDCs). a Select cytokines from an unbiased protein array profiling cytokine content within EDC conditioned media under hypoxic (1% oxygen) basal media conditions. *p < 0.05 vs. media conditioned by EDCs cultured within standard (STD) cell conditions. n=4 per group. b Select cytokines from an unbiased proteome array showing differential expression within media conditioned by STD EDCs and exSF Phys Env EDCs. *p < 0.05 vs. media conditioned by EDCs cultured within standard (STD) cell conditions. n=4 per group. c Effect of cell culture conditions on extracellular vesicle concentration and size. *p < 0.05 vs. all. N=3-4 per group. d Up and downregulated miRNAs in EVs isolated from exSF Phys Env EDCs compared to serum STD EDCs. n=3. FGF basic: Fibroblast growth factor basic; Flt-3: tyrosine kinase 3; GM-CSF: Granulocyte-macrophage colony-stimulating factor; HGF: Hepatocyte growth factor; ICAM: Intercellular adhesion molecule; IGFBP: Insulin-like growth factor binding protein; IL: interleukin; OPG: Osteoprotegerin; PDGF: Platelet-derived growth factor; SDF-1α: stromal cell-derived factor 1 alpha; uPAR: urokinase-type plasminogen activator; VEGF: Vascular endothelial growth hormoneCC BY · PubMed Central
Fig. 6 The rationale for autologous heart-derived cell therapy. a Schematic comparison of traditional centralized cell manufacturing with the decentralized cytocentric strategy afforded through modular physiologic GMP serum-free cell culture. b Conceptual promise of all cell therapies (blue line) to restore function and prolong survival contrasted with the dismal prognosis conferred after first hospitalization for heart failure. c Schematic outline of the real world effect of heart failure on physical function ranging between excellent and death (ordinate) as a function of time (abscissa) from cardiac injury. The influence of early medical therapy and progressive functional decline is contrasted between young (black line) and aged (gray line) patients. The ability of autologous heart-derived cell therapy (blue line) to partially restore function is shown which results in a functional deficit that for an elderly patient is not very much different from baseline. Figure modified from Goodlin with permission [43]
Fig. 6 The rationale for autologous heart-derived cell therapy. a Schematic comparison of traditional centralized cell manufacturing with the decentralized cytocentric strategy afforded through modular physiologic GMP serum-free cell culture. b Conceptual promise of all cell therapies (blue line) to restore function and prolong survival contrasted with the dismal prognosis conferred after first hospitalization for heart failure. c Schematic outline of the real world effect of heart failure on physical function ranging between excellent and death (ordinate) as a function of time (abscissa) from cardiac injury. The influence of early medical therapy and progressive functional decline is contrasted between young (black line) and aged (gray line) patients. The ability of autologous heart-derived cell therapy (blue line) to partially restore function is shown which results in a functional deficit that for an elderly patient is not very much different from baseline. Figure modified from Goodlin with permission [43]CC BY · PubMed Central

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Metadata

Authors
Mount, S., Kanda, P., Parent, S., Khan, S., Michie, C., Davila, L., Chan, V., Davies, R. A., Haddad, H., Courtman, D., Stewart, D. J., & Davis, D. R.
ORCID
Davis, Darryl R.
Venue
Stem Cell Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2019-11-04
Volume
10
Issue
1
ISSN
1757-6512
DOI
10.1186/s13287-019-1418-3
PMC
PMC6829847
Cited by
12
References
4
Language
en
Licence
Funders
  • Canadian Institutes of Health Research (PJT-162088, MC2-121291, Frederick Banting and Charles Best Canada Graduate Scholarship)
  • Stem Cell Network (NA)

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