Human adult HSCs can be discriminated from lineage-committed HPCs by the expression of endomucin – University of Copenhagen

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30 July 2018

Human adult HSCs can be discriminated from lineage-committed HPCs by the expression of endomucin

Reckzeh, Kristian, Hüsün Kizilkaya, Alexandra Søgaard Helbo, Montserrat Estruch Alrich, André Gundersen Deslauriers, Amit Grover, Nicolas Rapin, Fazila Asmar, Kirsten Grønbæk, Bo Porse, Niels Borregaard, Dietmar Vestweber, Claus Nerlov & Kim Theilgaard-Mönch (2018). Human adult HSCs can be discriminated from lineage-committed HPCs by the expression of endomucin. Blood Adv. 2(13), 1628-1632, doi: 10.1182/bloodadvances.2018015743

Introduction

Hematopoietic stem cells (HSCs) promote the lifelong production of all mature blood cell lineages through their unique capabilities of durable self-renewal and multilineage differentiation.1 Given the extensive regenerative property of HSCs, various types of stem-cell products have been successfully used in the clinic for cellular and genetic therapies for >4 decades.2 These include donor-derived bone marrow (BM), cord blood (CB), and mobilized peripheral blood stem-cell products for allogeneic stem-cell transplantation (SCT) in patients with hematological malignancies and monogenic diseases. Moreover, patient-derived peripheral blood stem-cell products are extensively used for autologous SCT supporting hematopoietic rescue after high-dose chemotherapy for various types of hematological malignancies, solid tumors, and autoimmune diseases.3 Significantly, the development of improved viral gene transduction protocols targeting HSCs has led to successful outcomes of gene therapies for monogenic diseases of the hematopoietic system, such as severe combined immunodeficiency, β-thalassemia, Wiskott-Aldrich syndrome, and leukodystrophy.4

Despite the outstanding clinical success of cellular and genetic HSC therapies, much of our knowledge of human adult HSC biology derives from mouse studies and studies of CB HSCs, because HSCs can only be identified and quantified operationally by functional transplantation assays, raising an obvious obstacle for studies of human adult HSCs, which, compared with murine HSCs and human CB HSCs, engraft relatively poorly in syngenic or xenotransplantation assays, respectively.5

As evidenced by clinical and xenotransplantation studies, all human HSCs as well as lineage-committed hematopoietic progenitor cells (HPCs) express CD34, although they lack expression of mature blood-cell lineage markers (L-34+).6 Significantly, L-34+ cells can be further subdivided by a series of surface markers into L-34+38+populations enriched in HPCs committed to the myeloid and lymphoid lineages, as well as L-34+38− populations enriched in progenitors with mixed lymphocyte and myeloid (monocytic) potential (LMPPs; L-34+38−45RA+90−), multipotent progenitors (MPPs; L-34+38−45RA−90−) with limited multilineage engraftment potential, and functional human HSCs (L-34+38−45RA−90+) with the capability of long-term multilineage engraftment.7,8 Given these premises, identification of novel HSC markers allowing for further refinement of the immunophenotype and an improved purification of adult HSCs is instrumental to gain new insights into human HSC biology and improve both HSC quantification and HSC graft engineering in the clinical setting.