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Article ; Online: The fulfilled promise and unmet potential of umbilical cord blood.

Ropa, James / Van't Hof, Wouter

2024

Abstract: Purpose of review: Here, we review classic and emerging uses of umbilical cord blood and highlight strategies to improve its utility, focusing on selection of the appropriate units and cell types for the intended applications.: Recent literature: ... ...

Abstract	Purpose of review: Here, we review classic and emerging uses of umbilical cord blood and highlight strategies to improve its utility, focusing on selection of the appropriate units and cell types for the intended applications. Recent literature: Recent studies have shown advancements in cord blood cell utility in a variety of cellular therapies and have made strides in elucidating manners to select the best units for therapy and target new ways to improve the various cell subpopulations for their respective applications. Summary: Umbilical cord blood is a proven source of cells for hematopoietic cell transplantation and research and is an important potential source for additional cellular therapies. However, cord blood utility is limited by low "doses" of potent cells that can be obtained from individual units, a limitation that is specific to cord blood as a donor source. In addition to traditional CD34+ progenitor cells, cord blood lymphocytes are being pursued as therapeutic entities with their own unique properties and characteristics. Thus, selection of ideal units depends on the intended therapeutic entity and target, and identification of differential potency parameters is critical to drive effective banking strategies accommodating successful clinical use of cord blood in broader cell therapy settings.
Language	English
Publishing date	2024-04-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	1153887-9
ISSN	1531-7048 ; 1065-6251
ISSN (online)	1531-7048
ISSN	1065-6251
DOI	10.1097/MOH.0000000000000817
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Article ; Online: Protocol for enrichment and functional analysis of human hematopoietic cells from umbilical cord blood.

Gutch, Sarah / Beasley, Lindsay / Cooper, Scott / Kaplan, Mark H / Capitano, Maegan L / Ropa, James

STAR protocols

2024 Volume 5, Issue 2, Page(s) 103024

Abstract: Umbilical cord blood (CB) is a donor source for hematopoietic cell therapies. Understanding what drives hematopoietic stem and progenitor cell function is critical to our understanding of the usage of CB in hematopoietic cell therapies. Here, we describe ...

Abstract	Umbilical cord blood (CB) is a donor source for hematopoietic cell therapies. Understanding what drives hematopoietic stem and progenitor cell function is critical to our understanding of the usage of CB in hematopoietic cell therapies. Here, we describe how to isolate and analyze the function of human hematopoietic cells from umbilical CB. This protocol demonstrates assays that measure phenotypic properties and hematopoietic cell potency. For complete details on the use and execution of this protocol, please refer to Broxmeyer et al.
Language	English
Publishing date	2024-04-23
Publishing country	United States
Document type	Journal Article
ISSN	2666-1667
ISSN (online)	2666-1667
DOI	10.1016/j.xpro.2024.103024
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Article ; Online: Leukemia Inhibitory Factor Promotes Survival of Hematopoietic Progenitors Ex Vivo and Is Post-Translationally Regulated by DPP4.

Ropa, James / Cooper, Scott / Broxmeyer, Hal E

Stem cells (Dayton, Ohio)

2022 Volume 40, Issue 3, Page(s) 346–357

Abstract: Hematopoietic cells are regulated in part by extracellular cues from cytokines. Leukemia inhibitory factor (LIF) promotes survival, self-renewal, and pluripotency of mouse embryonic stem cells (mESC). While genetic deletion of LIF affects hematopoietic ... ...

Abstract	Hematopoietic cells are regulated in part by extracellular cues from cytokines. Leukemia inhibitory factor (LIF) promotes survival, self-renewal, and pluripotency of mouse embryonic stem cells (mESC). While genetic deletion of LIF affects hematopoietic progenitor cells (HPCs), the direct effect of LIF protein exposure on HPC survival is not known. Furthermore, post-translational modifications (PTM) of LIF and their effects on its function have not been evaluated. We demonstrate that treatment with recombinant LIF preserves mouse and human HPC numbers in stressed conditions when growth factor addition is delayed ex vivo. We show that Lif is upregulated in response to irradiation-induced stress. We reveal novel PTM of LIF where it is cleaved twice by dipeptidyl peptidase 4 (DPP4) protease so that it loses its 4 N-terminal amino acids. This truncation of LIF down-modulates LIF's ability to preserve functional HPC numbers ex vivo following delayed growth factor addition. DPP4-truncated LIF blocks the ability of full-length LIF to preserve functional HPC numbers. This LIF role and its novel regulation by DPP4 have important implications for normal and stress hematopoiesis, as well as for other cellular contexts in which LIF and DPP4 are implicated.
MeSH term(s)	Animals ; Dipeptidyl Peptidase 4/genetics ; Dipeptidyl Peptidase 4/metabolism ; Hematopoiesis ; Hematopoietic Stem Cells/metabolism ; Humans ; Intercellular Signaling Peptides and Proteins ; Leukemia Inhibitory Factor/metabolism ; Leukemia Inhibitory Factor/pharmacology ; Mice
Chemical Substances	Intercellular Signaling Peptides and Proteins ; Leukemia Inhibitory Factor ; DPP4 protein, human (EC 3.4.14.5) ; Dipeptidyl Peptidase 4 (EC 3.4.14.5) ; Dpp4 protein, mouse (EC 3.4.14.5)
Language	English
Publishing date	2022-03-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1143556-2
ISSN	1549-4918 ; 1066-5099
ISSN (online)	1549-4918
ISSN	1066-5099
DOI	10.1093/stmcls/sxac004
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Article ; Online: An expanded role for dipeptidyl peptidase 4 in cell regulation.

Ropa, James / Broxmeyer, Hal E

Current opinion in hematology

2020 Volume 27, Issue 4, Page(s) 215–224

Abstract: Purpose of review: Dipeptidyl peptidase 4 (DPP4) is a serine protease with diverse regulatory functions in healthy and diseased cells. Much remains unknown about the mechanisms and targets of DPP4. Here we discuss new studies exploring DPP4-mediated ... ...

Abstract	Purpose of review: Dipeptidyl peptidase 4 (DPP4) is a serine protease with diverse regulatory functions in healthy and diseased cells. Much remains unknown about the mechanisms and targets of DPP4. Here we discuss new studies exploring DPP4-mediated cellular regulation, provide an updated list of potential targets of DPP4, and discuss clinical implications of each. Recent findings: Recent studies have sought enhanced efficacy of targeting DPP4's role in regulating hematopoietic stem and progenitor cells for improved clinical application. Further studies have identified DPP4 functions in different cellular compartments and have proposed ways to target this protein in malignancy. These findings, together with an expanded list of putative extracellular, cell surface, and intracellular DPP4 targets, provide insight into new DPP4-mediated cell regulation. Summary: DPP4 posttranslationally modifies proteins and peptides with essential roles in hematopoietic cell regulation, stem cell transplantation, and malignancy. Targets include secreted signaling factors and may include membrane proteins and transcription factors critical for different hematopoietic functions. Knowing these targets and functions can provide insight into new regulatory roles for DPP4 that may be targeted to enhance transplantation, treat disease, and better understand different regulatory pathways of hematopoiesis.
MeSH term(s)	Dipeptidyl Peptidase 4/genetics ; Dipeptidyl Peptidase 4/metabolism ; Hematopoiesis ; Hematopoietic Stem Cells/metabolism ; Hematopoietic Stem Cells/pathology ; Humans ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology
Chemical Substances	Neoplasm Proteins ; DPP4 protein, human (EC 3.4.14.5) ; Dipeptidyl Peptidase 4 (EC 3.4.14.5)
Keywords	covid19
Language	English
Publishing date	2020-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1153887-9
ISSN	1531-7048 ; 1065-6251
ISSN (online)	1531-7048
ISSN	1065-6251
DOI	10.1097/MOH.0000000000000590
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Article ; Online: CXCL15/Lungkine has suppressive activity on proliferation and expansion of multi-potential, erythroid, granulocyte and macrophage progenitors in S-phase specific manner.

Broxmeyer, Hal E / Cooper, Scott H / Ropa, James

Blood cells, molecules & diseases

2021 Volume 91, Page(s) 102594

Abstract: Cytokines/chemokines regulate hematopoiesis, most having multiple cell actions. Numerous but not all chemokine family members act as negative regulators of hematopoietic progenitor cell (HPC) proliferation, but very little is known about such effects of ... ...

Abstract	Cytokines/chemokines regulate hematopoiesis, most having multiple cell actions. Numerous but not all chemokine family members act as negative regulators of hematopoietic progenitor cell (HPC) proliferation, but very little is known about such effects of the chemokine, CXCL15/Lungkine. We found that CXCL15/Lungkine-/- mice have greatly increased cycling of multi cytokine-stimulated bone marrow and spleen hematopoietic progenitor cells (HPCs: CFU-GM, BFU-E, and CFU-GEMM) and CXCL15 is expressed in many bone marrow progenitor and other cell types. This suggests that CXCL15/Lungkine acts as a negative regulator of the cell cycling of these HPCs in vivo. Recombinant murine CXCL15/Lungkine, decreased numbers of functional HPCs during cytokine-enhanced ex-vivo culture of lineage negative mouse bone marrow cells. Moreover, CXCL15/Lungkine, through S-Phase specific actions, was able to suppress in vitro colony formation of normal wildtype mouse bone marrow CFU-GM, CFU-G, CFU-M, BFU-E, and CFU-GEMM. This clearly identifies the negative regulatory activity of CXCL15/Lungkine on proliferation of multiple types of mouse HPCs.
MeSH term(s)	Animals ; Cell Proliferation ; Cells, Cultured ; Chemokines, CXC/metabolism ; Erythroid Cells/cytology ; Erythroid Cells/metabolism ; Granulocytes/cytology ; Granulocytes/metabolism ; Macrophages/cytology ; Macrophages/metabolism ; Mice, Inbred C57BL ; S Phase Cell Cycle Checkpoints ; Stem Cells/cytology ; Stem Cells/metabolism ; Mice
Chemical Substances	Chemokines, CXC ; Cxcl15 protein, mouse
Language	English
Publishing date	2021-07-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1237083-6
ISSN	1096-0961 ; 1079-9796
ISSN (online)	1096-0961
ISSN	1079-9796
DOI	10.1016/j.bcmd.2021.102594
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Zs.A 1138: Show issues

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Article ; Online: Age-related decline in LEPR

Trinh, Thao / Ropa, James / Cooper, Scott / Aljoufi, Arafat / Sinn, Anthony / Capitano, Maegan / Broxmeyer, Hal E / Kaplan, Mark H

Leukemia

2023 Volume 37, Issue 3, Page(s) 712–716

MeSH term(s)	Humans ; Aging ; Hematopoietic Stem Cells
Chemical Substances	LEPR protein, human
Language	English
Publishing date	2023-01-17
Publishing country	England
Document type	Letter ; Research Support, N.I.H., Extramural
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-023-01815-1
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Zs.A 2295: Show issues

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Article ; Online: Consequences of coronavirus infections for primitive and mature hematopoietic cells: new insights and why it matters.

Ropa, James / Trinh, Thao / Aljoufi, Arafat / Broxmeyer, Hal E

Current opinion in hematology

2021 Volume 28, Issue 4, Page(s) 231–242

Abstract: Purpose of review: In recent history there have been three outbreaks of betacoronavirus infections in humans, with the most recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; causing Coronavirus disease 2019 [COVID-19]) outbreak leading ...

Abstract	Purpose of review: In recent history there have been three outbreaks of betacoronavirus infections in humans, with the most recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; causing Coronavirus disease 2019 [COVID-19]) outbreak leading to over two million deaths, with a rapidly rising death toll. Much remains unknown about host cells and tissues affected by coronavirus infections, including the hematopoietic system. Here, we discuss the recent findings examining effects that coronavirus infection or exposure has on hematopoietic cells and the clinical implications for these effects. Recent findings: Recent studies have centered on SARS-CoV-2, demonstrating that hematopoietic stem and progenitor cells and mature immune cells may be susceptible to infection and are impacted functionally by exposure to SARS-CoV-2 Spike protein. These findings have important implications regarding hematologic complications arising from COVID-19 and other coronavirus-induced disease, which we discuss here. Summary: Infection with coronaviruses sometimes leads to hematologic complications in patients, and these hematologic complications are associated with poorer prognosis. These hematologic complications may be caused by coronavirus direct infection or impact on primitive hematopoietic cells or mature immune cells, by indirect effects on these cells, or by a combination thereof. It is important to understand how hematologic complications arise in order to seek new treatments to improve patient outcomes.
MeSH term(s)	COVID-19/metabolism ; COVID-19/mortality ; COVID-19/pathology ; Hematopoietic Stem Cells/metabolism ; Hematopoietic Stem Cells/pathology ; Humans ; SARS-CoV-2/metabolism ; Spike Glycoprotein, Coronavirus/metabolism
Chemical Substances	Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2021-03-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1153887-9
ISSN	1531-7048 ; 1065-6251
ISSN (online)	1531-7048
ISSN	1065-6251
DOI	10.1097/MOH.0000000000000645
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Article ; Online: DEK, a nuclear protein, is chemotactic for hematopoietic stem/progenitor cells acting through CXCR2 and Gαi signaling.

Capitano, Maegan L / Sammour, Yasser / Ropa, James / Legendre, Maureen / Mor-Vaknin, Nirit / Markovitz, David M

Journal of leukocyte biology

2022 Volume 112, Issue 3, Page(s) 449–456

Abstract: Few cytokines/growth modulating proteins are known to be chemoattractants for hematopoietic stem (HSC) and progenitor cells (HPC); stromal cell-derived factor 1α (SDF1α/CXCL12) being the most potent known such protein. DEK, a nuclear DNA-binding ... ...

Abstract	Few cytokines/growth modulating proteins are known to be chemoattractants for hematopoietic stem (HSC) and progenitor cells (HPC); stromal cell-derived factor 1α (SDF1α/CXCL12) being the most potent known such protein. DEK, a nuclear DNA-binding chromatin protein with hematopoietic cytokine-like activity, is a chemotactic factor attracting mature immune cells. Transwell migration assays were performed to test whether DEK serves as a chemotactic agent for HSC/HPC. DEK induced dose- and time-dependent directed migration of lineage negative (Lin
MeSH term(s)	Bone Marrow Cells/metabolism ; Chemotaxis ; DNA-Binding Proteins/metabolism ; Hematopoietic Stem Cells/metabolism ; Nuclear Proteins/metabolism ; Receptors, Interleukin-8B/metabolism
Chemical Substances	DNA-Binding Proteins ; Nuclear Proteins ; Receptors, Interleukin-8B
Language	English
Publishing date	2022-02-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	605722-6
ISSN	1938-3673 ; 0741-5400
ISSN (online)	1938-3673
ISSN	0741-5400
DOI	10.1002/JLB.3AB1120-740R
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Article: An expanded role for dipeptidyl peptidase 4 in cell regulation

Ropa, James / Broxmeyer, Hal E

Curr Opin Hematol

Abstract: PURPOSE OF REVIEW: Dipeptidyl peptidase 4 (DPP4) is a serine protease with diverse regulatory functions in healthy and diseased cells. Much remains unknown about the mechanisms and targets of DPP4. Here we discuss new studies exploring DPP4-mediated ... ...

Abstract	PURPOSE OF REVIEW: Dipeptidyl peptidase 4 (DPP4) is a serine protease with diverse regulatory functions in healthy and diseased cells. Much remains unknown about the mechanisms and targets of DPP4. Here we discuss new studies exploring DPP4-mediated cellular regulation, provide an updated list of potential targets of DPP4, and discuss clinical implications of each. RECENT FINDINGS: Recent studies have sought enhanced efficacy of targeting DPP4's role in regulating hematopoietic stem and progenitor cells for improved clinical application. Further studies have identified DPP4 functions in different cellular compartments and have proposed ways to target this protein in malignancy. These findings, together with an expanded list of putative extracellular, cell surface, and intracellular DPP4 targets, provide insight into new DPP4-mediated cell regulation. SUMMARY: DPP4 posttranslationally modifies proteins and peptides with essential roles in hematopoietic cell regulation, stem cell transplantation, and malignancy. Targets include secreted signaling factors and may include membrane proteins and transcription factors critical for different hematopoietic functions. Knowing these targets and functions can provide insight into new regulatory roles for DPP4 that may be targeted to enhance transplantation, treat disease, and better understand different regulatory pathways of hematopoiesis.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #620675
Database	COVID19

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Article ; Online: CaMKK2 Knockout Bone Marrow Cells Collected/Processed in Low Oxygen (Physioxia) Suggests CaMKK2 as a Hematopoietic Stem to Progenitor Differentiation Fate Determinant.

Broxmeyer, Hal E / Ropa, James / Capitano, Maegan L / Cooper, Scott / Racioppi, Luigi / Sankar, Uma

Stem cell reviews and reports

2022 Volume 18, Issue 7, Page(s) 2513–2521

Abstract: Little is known about a regulatory role of CaMKK2 for hematopoietic stem (HSC) and progenitor (HPC) cell function. To assess this, we used Camkk2-/- and wild type (WT) control mouse bone marrow (BM) cells. BM cells were collected/processed and compared ... ...

Abstract	Little is known about a regulatory role of CaMKK2 for hematopoietic stem (HSC) and progenitor (HPC) cell function. To assess this, we used Camkk2-/- and wild type (WT) control mouse bone marrow (BM) cells. BM cells were collected/processed and compared under hypoxia (3% oxygen; physioxia) vs. ambient air (~21% oxygen). Subjecting cells collected to ambient air, even for a few minutes, causes a stress that we termed Extra Physiological Shock/Stress (EPHOSS) that causes differentiation of HSCs and HPCs. We consider physioxia collection/processing a more relevant way to assess HSC/HPC numbers and function, as the cells remain in an oxygen tension closer physiologic conditions. Camkk2-/- cells collected/processed at 3% oxygen had positive and negative effects respectively on HSCs (by engraftment using competitive transplantation with congenic donor and competitor cells and lethally irradiated congenic recipient mice), and HPCs (by colony forming assays of CFU-GM, BFU-E, and CFU-GEMM) compared to WT cells processed in ambient air. Thus, with cells collected/processed under physioxia, and therefore never exposed and naïve to ambient air conditions, CaMKK2 not only appears to act as an HSC to HPC differentiation fate determinant, but as we found for other intracellular mediators, the Camkk-/- mouse BM cells were relatively resistant to effects of EPHOSS. This information is of potential use for modulation of WT BM HSCs and HPCs for future clinical advantage.
MeSH term(s)	Animals ; Bone Marrow Cells ; Calcium-Calmodulin-Dependent Protein Kinase Kinase/genetics ; Hematopoietic Stem Cell Transplantation ; Mice ; Mice, Knockout ; Oxygen/pharmacology
Chemical Substances	Calcium-Calmodulin-Dependent Protein Kinase Kinase (EC 2.7.11.17) ; Camkk2 protein, mouse (EC 2.7.11.17) ; Oxygen (S88TT14065)
Language	English
Publishing date	2022-03-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2495577-2
ISSN	2629-3277 ; 1558-6804 ; 1550-8943
ISSN (online)	2629-3277 ; 1558-6804
ISSN	1550-8943
DOI	10.1007/s12015-021-10306-8
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