Injectable Materials for the Treatment of Myocardial Infarction and Heart Failure: The Promise of Decellularized Matrices

Cardiovascular disease continues to be the leading cause of death, suggesting that new therapies are needed to treat the progression of heart failure post-myocardial infarction. As cardiac tissue has a limited ability to regenerate itself, experimental biomaterial therapies have focused on the replacement of necrotic cardiomyocytes and repair of the damaged extracellular matrix. While acellular and cellular cardiac patches are applied surgically to the epicardial surface of the heart, injectable materials offer the prospective advantage of minimally invasive delivery directly into the myocardium to either replace the damaged extracellular matrix or to act as a scaffold for cell delivery. Cardiac-specific decellularized matrices offer the further advantage of being biomimetic of the native biochemical and structural matrix composition, as well as the potential to be autologous therapies. This review will focus on the requirements of an ideal scaffold for catheter-based delivery as well as highlight the promise of decellularized matrices as injectable materials for cardiac repair

Biomaterial Approaches for Stem Cell-Based Myocardial Tissue Engineering

Adult and pluripotent stem cells represent a ready supply of cellular raw materials that can be used to generate the functionally mature cells needed to replace damaged or diseased heart tissue. However, the use of stem cells for cardiac regenerative therapies is limited by the low efficiency by which stem cells are differentiated in vitro to cardiac lineages as well as the inability to effectively deliver stem cells and their derivatives to regions of damaged myocardium. In this review, we discuss the various biomaterial-based approaches that are being implemented to direct stem cell fate both in vitro and in vivo . First, we discuss the stem cell types available for cardiac repair and the engineering of naturally and synthetically derived biomaterials to direct their in vitro differentiation to the cell types that comprise heart tissue. Next, we describe biomaterial-based approaches that are being implemented to enhance the in vivo integration and differentiation of stem cells delivered to areas of cardiac damage. Finally, we present emerging trends of using stem cell-based biomaterial approaches to deliver pro-survival factors and fully vascularized tissue to the damaged and diseased cardiac tissue

Endogenous WNT Signaling Regulates hPSC-Derived Neural Progenitor Cell Heterogeneity and Specifies Their Regional Identity

Neural progenitor cells (NPCs) derived from human pluripotent stem cells (hPSCs) are a multipotent cell population that is capable of nearly indefinite expansion and subsequent differentiation into the various neuronal and supporting cell types that comprise the CNS. However, current protocols for differentiating NPCs toward neuronal lineages result in a mixture of neurons from various regions of the CNS. In this study, we determined that endogenous WNT signaling is a primary contributor to the heterogeneity observed in NPC cultures and neuronal differentiation. Furthermore, exogenous manipulation of WNT signaling during neural differentiation, through either activation or inhibition, reduces this heterogeneity in NPC cultures, thereby promoting the formation of regionally homogeneous NPC and neuronal cultures. The ability to manipulate WNT signaling to generate regionally specific NPCs and neurons will be useful for studying human neural development and will greatly enhance the translational potential of hPSCs for neural-related therapies

Generation and characterization of two human induced pluripotent stem cell (hiPSC) lines homozygous for the Apolipoprotein e4 (APOE4) risk variant—Alzheimer's disease (ASUi005-A) and healthy non-demented control (ASUi006-A)

Although the majority of late-onset Alzheimer's disease (AD) patients are labeled sporadic, multiple genetic risk variants have been identified, the most powerful and prevalent of which is the e4 variant of the Apolipoprotein E (APOE) gene. Here, we generated human induced pluripotent stem cell (hiPSC) lines from the peripheral blood mononuclear cells (PBMCs) of a clinically diagnosed AD patient [ASUi005-A] and a non-demented control (NDC) patient [ASUi006-A] homozygous for the APOE4 risk allele. These hiPSCs maintained their original genotype, expressed pluripotency markers, exhibited a normal karyotype, and retained the ability to differentiate into cells representative of the three germ layers.Resource tableUnlabelled TableUnique stem cell lines identifierASUi005-AASUi006-AAlternative names of stem cell linesASU-161ASU-487InstitutionArizona State University; Tempe, AZ; USAContact information of distributorDavid Brafman, [email protected] of cell linesiPSCOriginHumanCell sourceHuman peripheral blood mononuclear cells (PBMCs)ClonalityClonalMethod of reprogrammingCytoTune®-iPS 2.0 Reprogramming SystemMultiline rationaleAge-matched Alzheimer's disease and non-demented control hiPSC lines homozygous for the APOE 4 risk factorGene modificationNoType of modificationN/AAssociated diseaseAlzheimer's diseaseGene/locusApolipoprotein E (APOE)Method of modificationN/AName of transgene or resistanceN/AInducible/constitutive systemN/ADate archived/stock dateMarch 2018Cell line repository/bankNot applicableEthical approvalMayo Clinic Institutional Review Board; IRB # 15-00867

Generation and characterization of human induced pluripotent stem cell (hiPSC) lines from an Alzheimer's disease (ASUi003-A) and non-demented control (ASUi004-A) patient homozygous for the Apolipoprotein e4 (APOE4) risk variant

Although the majority of late-onset Alzheimer's disease (AD) patients are labeled sporadic, multiple genetic risk variants have been identified, the most powerful and prevalent of which is the e4 variant of the Apolipoprotein E (APOE) gene. Here, we generated human induced pluripotent stem cell (hiPSC) lines from the peripheral blood mononuclear cells (PBMCs) of a clinically diagnosed AD patient [ASUi003-A] and a non-demented control (NDC) patient [ASUi004-A] homozygous for the APOE4 risk allele. These hiPSCs maintained their original genotype, expressed pluripotency markers, exhibited a normal karyotype, and retained the ability to differentiate into cells representative of the three germ layers

Generation and characterization of human induced pluripotent stem cell (hiPSC) lines from an Alzheimer's disease (ASUi001-A) and non-demented control (ASUi002-A) patient homozygous for the Apolipoprotein e4 (APOE4) risk variant

Although the majority of late-onset Alzheimer's disease (AD) patients are labeled sporadic, multiple genetic risk variants have been identified, the most powerful and prevalent of which is the e4 variant of the Apolipoprotein E (APOE) gene. Here, we generated human induced pluripotent stem cell (hiPSC) lines from the peripheral blood mononuclear cells (PBMCs) of a clinically diagnosed AD patient [ASUi001-A] and a non-demented control (NDC) patient [ASUi002-A] homozygous for the APOE4 risk allele. These hiPSCs maintained their original genotype, expressed pluripotency markers, exhibited a normal karyotype, and demonstrated the ability to differentiate into cells representative of the three germ layers

A chemically defined substrate for the expansion and neuronal differentiation of human pluripotent stem cell-derived neural progenitor cells

Due to the limitation of current pharmacological therapeutic strategies, stem cell therapies have emerged as a viable option for treating many incurable neurological disorders. Specifically, human pluripotent stem cell (hPSC)-derived neural progenitor cells (hNPCs), a multipotent cell population that is capable of near indefinite expansion and subsequent differentiation into the various cell types that comprise the central nervous system (CNS), could provide an unlimited source of cells for such cell-based therapies. However the clinical application of these cells will require (i) defined, xeno-free conditions for their expansion and neuronal differentiation and (ii) scalable culture systems that enable their expansion and neuronal differentiation in numbers sufficient for regenerative medicine and drug screening purposes. Current extracellular matrix protein (ECMP)-based substrates for the culture of hNPCs are expensive, difficult to isolate, subject to batch-to-batch variations, and, therefore, unsuitable for clinical application of hNPCs. Using a high-throughput array-based screening approach, we identified a synthetic polymer, poly(4-vinyl phenol) (P4VP), that supported the long-term proliferation and self-renewal of hNPCs. The hNPCs cultured on P4VP maintained their characteristic morphology, expressed high levels of markers of multipotency, and retained their ability to differentiate into neurons. Such chemically defined substrates will eliminate critical roadblocks for the utilization of hNPCs for human neural regenerative repair, disease modeling, and drug discovery