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Preconditioning Human Adipose-Derived Stromal Cells On Decellularized Adipose Tissue Scaffolds Within A Perfusion Bioreactor Modulates Cell Phenotype And Promotes A Pro-Regenerative Host Response, Tim Tian Y. Han, John T. Walker, Aaron Grant, Gregory A. Dekaban, Lauren E. Flynn
Preconditioning Human Adipose-Derived Stromal Cells On Decellularized Adipose Tissue Scaffolds Within A Perfusion Bioreactor Modulates Cell Phenotype And Promotes A Pro-Regenerative Host Response, Tim Tian Y. Han, John T. Walker, Aaron Grant, Gregory A. Dekaban, Lauren E. Flynn
Paediatrics Publications
Cell-based therapies involving the delivery of adipose-derived stromal cells (ASCs) on decellularized adipose tissue (DAT) scaffolds are a promising approach for soft tissue augmentation and reconstruction. Our lab has recently shown that culturing human ASCs on DAT scaffolds within a perfusion bioreactor prior to implantation can enhance their capacity to stimulate in vivo adipose tissue regeneration. Building from this previous work, the current study investigated the effects of bioreactor preconditioning on the ASC phenotype and secretory profile in vitro, as well as host cell recruitment following implantation in an athymic nude mouse model. Immunohistochemical analyses indicated that culturing within the …
The Long Non-Coding Rna Hotair Is A Critical Epigenetic Mediator Of Angiogenesis In Diabetic Retinopathy, Saumik Biswas, Biao Feng, Shali Chen, Jieting Liu, Erfan Aref-Eshghi, John Gonder, Vy Ngo, Bekim Sadikovic, Subrata Chakrabarti
The Long Non-Coding Rna Hotair Is A Critical Epigenetic Mediator Of Angiogenesis In Diabetic Retinopathy, Saumik Biswas, Biao Feng, Shali Chen, Jieting Liu, Erfan Aref-Eshghi, John Gonder, Vy Ngo, Bekim Sadikovic, Subrata Chakrabarti
Paediatrics Publications
PURPOSE. Diabetic retinopathy (DR) remains a pressing issue worldwide. Abnormal angiogenesis is a distinct vascular lesion in DR, and research has established that vascular endothelial growth factor A (VEGF-A) is a primary mediator of such changes. However, limitations in current anti-VEGF therapies suggest that our understanding of molecular networks underlying ocular angiogenesis remains far from complete. Based on our long non-coding RNA (lncRNA) array analyses, HOX antisense intergenic RNA (HOTAIR) was identified as one of the top upregulated lncRNAs in high glucose-cultured human retinal endothelial cells (HRECs). Given the well-documented roles of HOTAIR in cancer, no studies have examined the …
Perfusion Bioreactor Culture Of Human Adipose-Derived Stromal Cells On Decellularized Adipose Tissue Scaffolds Enhances In Vivo Adipose Tissue Regeneration, Tim Tian Y. Han, Lauren E. Flynn
Perfusion Bioreactor Culture Of Human Adipose-Derived Stromal Cells On Decellularized Adipose Tissue Scaffolds Enhances In Vivo Adipose Tissue Regeneration, Tim Tian Y. Han, Lauren E. Flynn
Paediatrics Publications
Tissue-engineering approaches hold promise to address the need in plastic and reconstructive surgery for new therapies that promote stable adipose tissue regeneration. Previous studies have demonstrated the potential of combining decellularized adipose tissue (DAT) scaffolds with adipose-derived stromal cells (ASCs) for volume augmentation applications. With the goal of enhancing in vivo angiogenesis and adipogenesis, this study evaluated the effects of culturing human ASCs on DAT scaffolds within a perfusion bioreactor. Using this system, the impact of both dynamic culture and hypoxic preconditioning were explored in vitro and in vivo. Initial studies compared the effects of 14 days of culture within …
Circulating Pro-Vascular Progenitor Cell Depletion During Type 2 Diabetes: Translational Insights Into The Prevention Of Ischemic Complications In Diabetes, Daniella C. Terenzi, Mohammed Al-Omran, Adrian Quan, Hwee Teoh, Subodh Verma, David A. Hess
Circulating Pro-Vascular Progenitor Cell Depletion During Type 2 Diabetes: Translational Insights Into The Prevention Of Ischemic Complications In Diabetes, Daniella C. Terenzi, Mohammed Al-Omran, Adrian Quan, Hwee Teoh, Subodh Verma, David A. Hess
Paediatrics Publications
Detection of vascular regenerative cell exhaustion is required to combat ischemic complications during type 2 diabetes mellitus (T2D). We used high aldehyde dehydrogenase (ALDH) activity and surface marker co-expression to develop a high-throughput flow cytometry–based assay to quantify circulating proangiogenic and proinflammatory cell content in the peripheral blood of individuals with T2D. Circulating proangiogenic monocytes expressing anti-inflammatory M2 markers were decreased in patients with T2D. Individuals with longer duration of T2D exhibited reduced frequencies of circulating proangiogenic ALDH hi CD34+ progenitor cells with primitive (CD133) and migratory (CXCR4) phenotypes. This approach consistently detected increased inflammatory cell burden and decreased provascular …
Concise Review: Cell Therapy For Critical Limb Ischemia: An Integrated Review Of Preclinical And Clinical Studies, Mohammad Qadura, Daniella C. Terenzi, Subodh Verma, Mohammed Al-Omran, David A. Hess
Concise Review: Cell Therapy For Critical Limb Ischemia: An Integrated Review Of Preclinical And Clinical Studies, Mohammad Qadura, Daniella C. Terenzi, Subodh Verma, Mohammed Al-Omran, David A. Hess
Paediatrics Publications
Critical limb ischemia (CLI), the most severe form of peripheral artery disease, is characterized by pain at rest and non-healing ulcers in the lower extremities. For patients with CLI, where the extent of atherosclerotic artery occlusion is too severe for surgical bypass or percutaneous interventions, limb amputation remains the only treatment option. Thus, cell-based therapy to restore perfusion and promote wound healing in patients with CLI is under intense investigation. Despite promising preclinical studies in animal models, transplantation of bone marrow (BM)-derived cell populations in patients with CLI has shown limited benefit preventing limb amputation. Early trials injected heterogenous mononuclear …
Proteomic Characterisation Reveals Active Wnt-Signalling By Human Multipotent Stromal Cells As A Key Regulator Of Beta Cell Survival And Proliferation, Miljan Kuljanin, Gillian I. Bell, Stephen E. Sherman, Gilles A. Lajoie, David A. Hess
Proteomic Characterisation Reveals Active Wnt-Signalling By Human Multipotent Stromal Cells As A Key Regulator Of Beta Cell Survival And Proliferation, Miljan Kuljanin, Gillian I. Bell, Stephen E. Sherman, Gilles A. Lajoie, David A. Hess
Paediatrics Publications
Aims/hypothesis: Novel strategies to stimulate the expansion of beta cell mass in situ are warranted for diabetes therapy. The aim of this study was to elucidate the secretome of human bone marrow (BM)-derived multipotent stromal cells (MSCs) with documented islet regenerative paracrine function. We hypothesised that regenerative MSCs will secrete a unique combination of protein factors that augment islet regeneration. Methods: Human BM-derived MSCs were examined for glucose-lowering capacity after transplantation into streptozotocin-treated NOD/severe combined immunodeficiency (SCID) mice and segregated into samples with regenerative (MSCR) vs nonregenerative (MSCNR) capacity. Secreted proteins associated with islet regenerative function were identified using stable …
Expansion Of Umbilical Cord Blood Aldehyde Dehydrogenase Expressing Cells Generates Myeloid Progenitor Cells That Stimulate Limb Revascularization, David M. Putman, Tyler T. Cooper, Stephen E. Sherman, Ayesh K. Seneviratne, Mark Hewitt, Gillian I. Bell, David A. Hess
Expansion Of Umbilical Cord Blood Aldehyde Dehydrogenase Expressing Cells Generates Myeloid Progenitor Cells That Stimulate Limb Revascularization, David M. Putman, Tyler T. Cooper, Stephen E. Sherman, Ayesh K. Seneviratne, Mark Hewitt, Gillian I. Bell, David A. Hess
Paediatrics Publications
Uncompromised by chronic disease-related comorbidities, human umbilical cord blood (UCB) progenitor cells with high aldehyde dehydrogenase activity (ALDHhi cells) stimulate blood vessel regeneration after intra-muscular transplantation. However, implementation of cellular therapies using UCB ALDHhi cells for critical limb ischemia, the most severe form of severe peripheral artery disease, is limited by the rarity (<0.5%) of these cells. Our goal was to generate a clinically-translatable, allogeneic cell population for vessel regenerative therapies, via ex vivo expansion of UCB ALDHhi cells without loss of pro-angiogenic potency. Purified UCB ALDHhi cells were expanded >18-fold over 6-days under serum-free conditions. Consistent with the concept that ALDH-activity is decreased as progenitor cells differentiate, only 15.1% ± 1.3% of progeny maintained high ALDH-activity after culture. However, compared to fresh UCB cells, expansion increased the total number of ALDHhi cells (2.7-fold), CD34+/CD133+ cells …
High Aldehyde Dehydrogenase Activity Identifies A Subset Of Human Mesenchymal Stromal Cells With Vascular Regenerative Potential, Stephen E. Sherman, Miljan Kuljanin, Tyler T. Cooper, David M. Putman, Gilles A. Lajoie, David A. Hess
High Aldehyde Dehydrogenase Activity Identifies A Subset Of Human Mesenchymal Stromal Cells With Vascular Regenerative Potential, Stephen E. Sherman, Miljan Kuljanin, Tyler T. Cooper, David M. Putman, Gilles A. Lajoie, David A. Hess
Paediatrics Publications
During culture expansion, multipotent mesenchymal stromal cells (MSCs) differentially express aldehyde dehydrogenase (ALDH), an intracellular detoxification enzyme that protects long-lived cells against oxidative stress. Thus, MSC selection based on ALDH-activity may be used to reduce heterogeneity and distinguish MSC subsets with improved regenerative potency. After expansion of human bone marrow-derived MSCs, cell progeny was purified based on low versus high ALDH-activity (ALDHhi) by fluorescence-activated cell sorting, and each subset was compared for multipotent stromal and provascular regenerative functions. Both ALDHl° and ALDHhi MSC subsets demonstrated similar expression of stromal cell (>95% CD73+, CD90+, CD105+) and pericyte (>95% CD146+) …
Mechanisms Of Trophoblast Migration, Endometrial Angiogenesis In Preeclampsia: The Role Of Decorin, Peeyush K. Lala, Pinki Nandi
Mechanisms Of Trophoblast Migration, Endometrial Angiogenesis In Preeclampsia: The Role Of Decorin, Peeyush K. Lala, Pinki Nandi
Paediatrics Publications
The objective of the present review is to synthesize the information on the cellular and molecular players responsible for maintaining a homeostatic balance between a naturally invasive human placenta and the maternal uterus in pregnancy; to review the roles of decorin (DCN) as a molecular player in this homeostasis; to list the common maladies associated with a break-down in this homeostasis, resulting from a hypo-invasive or hyper-invasive placenta, and their underlying mechanisms. We show that both the fetal components of the placenta, represented primarily by the extravillous trophoblast, and the maternal component represented primarily by the decidual tissue and the …
Mechanisms Of Propranolol Action In Infantile Hemangioma, Jina J.Y. Kum, Zia A. Khan
Mechanisms Of Propranolol Action In Infantile Hemangioma, Jina J.Y. Kum, Zia A. Khan
Paediatrics Publications
Infantile hemangioma is a common tumor of infancy. Although most hemangiomas spontaneously regress, treatment is indicated based on complications, risk to organ development and function, and disfigurement. The serendipitous discovery of propranolol, a non-selective b-adrenergic receptor blocker, as an effective means to regress hemangiomas has made this a first-line therapy for hemangioma patients. Propranolol has shown remarkable response rates. There are, however, some adverse effects, which include changes in sleep, acrocyanosis, hypotension, and hypoglycemia. Over the last few years, researchers have focused on understanding the mechanisms by which propranolol causes hemangioma regression. This has entailed study of cultured vascular endothelial …
Pathophysiological Role Of Enhanced Bone Marrow Adipogenesis In Diabetic Complications, Meghan A. Piccinin, Zia A. Khan
Pathophysiological Role Of Enhanced Bone Marrow Adipogenesis In Diabetic Complications, Meghan A. Piccinin, Zia A. Khan
Paediatrics Publications
Diabetes leads to complications in select organ systems primarily by disrupting the vasculature of the target organs. These complications include both micro-(cardiomyopathy, retinopathy, nephropathy, and neuropathy) and macro-(atherosclerosis) angiopathies. Bone marrow angiopathy is also evident in both experimental models of the disease as well as in human diabetes. In addition to vascular disruption, bone loss and increased marrow adiposity have become hallmarks of the diabetic bone phenotype. Emerging evidence now implicates enhanced marrow adipogenesis and changes to cellular makeup of the marrow in a novel mechanistic link between various secondary complications of diabetes. In this review, we explore the mechanisms …
Umbilical Cord Blood-Derived Aldehyde Dehydrogenase-Expressing Progenitor Cells Promote Recovery From Acute Ischemic Injury, David M. Putman, Kevin Y. Liu, Heather C. Broughton, Gillian I. Bell, David A. Hess
Umbilical Cord Blood-Derived Aldehyde Dehydrogenase-Expressing Progenitor Cells Promote Recovery From Acute Ischemic Injury, David M. Putman, Kevin Y. Liu, Heather C. Broughton, Gillian I. Bell, David A. Hess
Paediatrics Publications
Umbilical cord blood (UCB) represents a readily available source of hematopoietic and endothelial precursors at early ontogeny. Understanding the proangiogenic functions of these somatic progenitor subtypes after transplantation is integral to the development of improved cell-based therapies to treat ischemic diseases. We used fluorescence-activated cell sorting to purify a rare (<0.5%) population of UCB cells with high aldehyde dehydrogenase (ALDHhi) activity, a conserved stem/progenitor cell function. ALDHhicells were depleted of mature monocytes and T- and B-lymphocytes and were enriched for early myeloid (CD33) and stem cell-associated (CD34, CD133, and CD117) phenotypes. Although these cells were primarily hematopoietic in origin, UCB ALDHhi cells demonstrated a proangiogenic transcription profile and were highly enriched for both multipotent myeloid and endothelial colony-forming cells in vitro. Coculture of ALDHhi cells in hanging transwells promoted the survival of human umbilical vein endothelial cells (HUVEC) under growth factor-free and serum-free conditions. On growth factor depleted matrigel, ALDHhicells significantly increased tube-like cord formation by HUVEC. After induction of acute unilateral hind limb ischemia by femoral artery ligation, transplantation of ALDHhi cells significantly enhanced the recovery of perfusion in ischemic limbs. Despite transient engraftment in the ischemic hind limb, early recruitment of ALDHhi cells into ischemic muscle tissue correlated with increased murine von Willebrand factor blood vessel and CD31+ capillary densities. Thus, UCB ALDHhi cells represent a readily available population of proangiogenic progenitors that promote vascular regeneration. This work provides preclinical justification for the development of therapeutic strategies to treat ischemic diseases using UCB-derived ALDH hi mixed progenitor cells. © AlphaMed Press.
Vascular Stem Cells In Diabetic Complications: Evidence For A Role In The Pathogenesis And The Therapeutic Promise, Emily C. Keats, Zia A. Khan
Vascular Stem Cells In Diabetic Complications: Evidence For A Role In The Pathogenesis And The Therapeutic Promise, Emily C. Keats, Zia A. Khan
Paediatrics Publications
Long standing diabetes leads to structural and functional alterations in both the micro- and the macro-vasculature. Vascular endothelial cells (ECs) are the primary target of the hyperglycemia-induced adverse effects. Vascular stem cells that give rise to endothelial progenitor cells (EPCs) and mesenchymal progenitor cells (MPCs) represent an attractive target for cell therapy for diabetic patients. A number of studies have reported EPC dysfunction as a novel participant in the culmination of the diabetic complications. The controversy behind the identity of EPCs and the similarity between these progenitor cells to hematopoietic cells has led to conflicting results. MPCs, on the other …