Rare multipotent haematopoietic stem cells (HSCs) in adult bone marrow with extensive self-renewal potential can efficiently replenish all myeloid and lymphoid blood cells(1), securing long-term multilineage reconstitution after physiological and clinical challenges such as chemotherapy and haematopoietic transplantations(2-4). HSC transplantation remains the only curative treatment for many haematological malignancies, but inefficient blood-lineage replenishment remains a major cause of morbidity and mortality(5,6). Single-cell transplantation has uncovered considerable heterogeneity among reconstituting HSCs7-11, a finding that is supported by studies of unperturbed haematopoiesis(2-4,12) and may reflect different propensities for lineage-fate decisions by distinct myeloid-, lymphoid-and platelet-biased HSCs7-10,13. Other studies suggested that such lineage bias might reflect generation of unipotent or oligopotent self-renewing progenitors within the phenotypic HSC compartment, and implicated uncoupling of the defining HSC properties of self-renewal and multipotency(11,14). Here we use highly sensitive tracking of progenitors and mature cells of the megakaryocyte/platelet, erythroid, myeloid and B and T cell lineages, produced from singly transplanted HSCs, to reveal a highly organized, predictable and stable framework for lineage-restricted fates of long-term self-renewing HSCs. Most notably, a distinct class of HSCs adopts a fate towards effective and stable replenishment of a megakaryocyte/platelet-lineage tree but not of other blood cell lineages, despite sustained multipotency. No HSCs contribute exclusively to any other single blood-cell lineage. Single multipotent HSCs can also fully restrict towards simultaneous replenishment of megakaryocyte, erythroid and myeloid lineages without executing their sustained lymphoid lineage potential. Genetic lineage-tracing analysis also provides evidence for an important role of plateletbiased HSCs in unperturbed adult haematopoiesis. These findings uncover a limited repertoire of distinct HSC subsets, defined by a predictable and hierarchical propensity to adopt a fate towards replenishment of a restricted set of blood lineages, before loss of self-renewal and multipotency.

Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells / Carrelha, Joana; Meng, Yiran; Kettyle, Laura M; Luis, Tiago C; Norfo, Ruggiero; Alcolea, Verónica; Boukarabila, Hanane; Grasso, Francesca; Gambardella, Adriana; Grover, Amit; Högstrand, Kari; Lord, Allegra M; Sanjuan-Pla, Alejandra; Woll, Petter S; Nerlov, Claus; Jacobsen, Sten Eirik W. - In: NATURE. - ISSN 1476-4687. - 554:7690(2018), pp. 106-111. [10.1038/nature25455]

Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells

Norfo, Ruggiero;
2018

Abstract

Rare multipotent haematopoietic stem cells (HSCs) in adult bone marrow with extensive self-renewal potential can efficiently replenish all myeloid and lymphoid blood cells(1), securing long-term multilineage reconstitution after physiological and clinical challenges such as chemotherapy and haematopoietic transplantations(2-4). HSC transplantation remains the only curative treatment for many haematological malignancies, but inefficient blood-lineage replenishment remains a major cause of morbidity and mortality(5,6). Single-cell transplantation has uncovered considerable heterogeneity among reconstituting HSCs7-11, a finding that is supported by studies of unperturbed haematopoiesis(2-4,12) and may reflect different propensities for lineage-fate decisions by distinct myeloid-, lymphoid-and platelet-biased HSCs7-10,13. Other studies suggested that such lineage bias might reflect generation of unipotent or oligopotent self-renewing progenitors within the phenotypic HSC compartment, and implicated uncoupling of the defining HSC properties of self-renewal and multipotency(11,14). Here we use highly sensitive tracking of progenitors and mature cells of the megakaryocyte/platelet, erythroid, myeloid and B and T cell lineages, produced from singly transplanted HSCs, to reveal a highly organized, predictable and stable framework for lineage-restricted fates of long-term self-renewing HSCs. Most notably, a distinct class of HSCs adopts a fate towards effective and stable replenishment of a megakaryocyte/platelet-lineage tree but not of other blood cell lineages, despite sustained multipotency. No HSCs contribute exclusively to any other single blood-cell lineage. Single multipotent HSCs can also fully restrict towards simultaneous replenishment of megakaryocyte, erythroid and myeloid lineages without executing their sustained lymphoid lineage potential. Genetic lineage-tracing analysis also provides evidence for an important role of plateletbiased HSCs in unperturbed adult haematopoiesis. These findings uncover a limited repertoire of distinct HSC subsets, defined by a predictable and hierarchical propensity to adopt a fate towards replenishment of a restricted set of blood lineages, before loss of self-renewal and multipotency.
2018
554
7690
106
111
Hierarchically related lineage-restricted fates of multipotent haematopoietic stem cells / Carrelha, Joana; Meng, Yiran; Kettyle, Laura M; Luis, Tiago C; Norfo, Ruggiero; Alcolea, Verónica; Boukarabila, Hanane; Grasso, Francesca; Gambardella, Adriana; Grover, Amit; Högstrand, Kari; Lord, Allegra M; Sanjuan-Pla, Alejandra; Woll, Petter S; Nerlov, Claus; Jacobsen, Sten Eirik W. - In: NATURE. - ISSN 1476-4687. - 554:7690(2018), pp. 106-111. [10.1038/nature25455]
Carrelha, Joana; Meng, Yiran; Kettyle, Laura M; Luis, Tiago C; Norfo, Ruggiero; Alcolea, Verónica; Boukarabila, Hanane; Grasso, Francesca; Gambardella, Adriana; Grover, Amit; Högstrand, Kari; Lord, Allegra M; Sanjuan-Pla, Alejandra; Woll, Petter S; Nerlov, Claus; Jacobsen, Sten Eirik W
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1292003
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