Long-term ex vivo haematopoietic-stem-cell expansion allows nonconditioned transplantation

Wilkinson, Adam C.; Ishida, Ryôhei; Kikuchi, Misako; Sudo, Kazuhiro; Morita, Mamoru; Crisostomo, Ralph Valentine; Yamamoto, Ryō; Loh, Kyle M.; Nakamura, Yukio; Watanabe, Motoó; Nakauchi, Hiromitsu; Yamazaki, Satoshi

doi:10.1038/s41586-019-1244-x

Cited by 308 publications

(355 citation statements)

References 29 publications

Supporting

Mentioning

347

Contrasting

Order By: Relevance

“…A recent paper reported the 899-fold in vitro expansion of mouse HSCs over the course of one month using cytokine supplementation and polyvinyl alcohol in the medium [79]. To date, the earliest HSCs that have been found to yield long-term, serial, multilineage engraftment in irradiated adult mice arise from the AGM on or around embryonic day 10.5 via EHT.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Haematopoietic stem cell reprogramming and the hope for a universal blood product

2019

View full text Add to dashboard Cite

Edited by Catherine RobinHaematopoietic stem cells (HSCs) are the only adult stem cells with a demonstrated clinical use, even though a tractable method to maintain and expand human HSCs in vitro has not yet been found. Owing to the introduction of transplantation strategies for the treatment of haematological malignancies and, more recently, the promise of gene therapy, the need to improve the generation, manipulation and scalability of autologous or allogeneic HSCs has risen steeply over the past decade. In that context, reprogramming strategies based on the expression of exogenous transcription factors have emerged as a means to produce functional HSCs in vitro. These approaches largely stem from the assumption that key master transcription factors direct the expression of downstream target genes thereby triggering haematopoiesis. Both somatic and pluripotent cells have been used to this end, yielding variable results in terms of haematopoietic phenotype and functionality. Here, we present an overview of the haematopoietic reprogramming methods reported to date, provide the appropriate historical context and offer some critical insight about where the field stands at present.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Whether HSCs can be expanded ex vivo remains a question. A recent paper reported the 899-fold in vitro expansion of mouse HSCs over the course of one month using cytokine supplementation and polyvinyl alcohol in the medium [79]. Human HSCs, however, were only shown to expand reliably for 7 days following the same method.…”

Section: Discussionmentioning

confidence: 99%

Haematopoietic stem cell reprogramming and the hope for a universal blood product

2019

View full text Add to dashboard Cite

show abstract

“…Several earlier stage CIRM awards have explored endogenous paracrine factors that might also be exploited to expand HSPCs in vivo or in vitro, such as pleiotrophin and dickkopf‐1 . Most recently, a CIRM funded exploratory study identified novel culture conditions permitting 236‐899‐fold expansion of highly engraftable, functional murine HSCs in only 30 days, and is currently attempting to replicate this phenomenon in a human HSC culture system (Table ). Although these endeavors are encouraging, each approach affects one or more different subpopulations of blood progenitors and the long‐term engraftability and clinical utility of expanded cells remains unknown.…”

Section: Limited Availability Of Hscs: Improving Donor Cell Sourcesmentioning

confidence: 99%

Unleashing the cure: Overcoming persistent obstacles in the translation and expanded use of hematopoietic stem cell-based therapies

Talib

Shepard

2020

Stem Cells Translational Medicine

View full text Add to dashboard Cite

Hematopoietic stem cell transplantation (HSCT) is broadly used for treating and curing hematological cancers and various disorders of the blood and immune system. However, its true therapeutic potential remains vastly constrained by significant scientific and technical hurdles that preclude expansion to new indications and limit the number of patients who could benefit from, gain access to, or financially afford the procedure. To define and overcome these challenges, the California Institute for Regenerative Medicine (CIRM) held multiple workshops related to HSCT and has subsequently invested in a new generation of approaches to address the most compelling needs of the field, including new sources of healthy and immunologically compatible hematopoietic stem cells for transplant; safe and efficient genome modification technologies for correction of inherited genetic defects and other forms of gene therapy; safer and more tractable transplantation procedures such as nongenotoxic conditioning regimens, methods to accelerate immune reconstitution and recovery of immune function, and innovations to minimize the risk of immune rejection; and other life‐threatening complications from transplant. This Perspective serves to highlight these needs through examples from the recent CIRM‐funded and other notable investigations, presents rationale for comprehensive, systematic, and focused strategies to unleash the full potential of HSCT, thereby enabling cures for a greatly expanded number of disorders and making HSCT feasible, accessible, and affordable to all who could benefit.

show abstract

“…Due to their ability to repopulate the entire hematopoietic system upon transplantation in both mice and humans, HSCs represent the currently established standard for stem cell therapy. To this end, several studies exist that employ different methods to expand these cells ex vivo or generate them de novo [10][11][12][13]. To this end, several studies exist that employ different methods to expand these cells ex vivo or generate them de novo [10][11][12][13].…”

mentioning

confidence: 99%

“…The source material required for these applications, however, remains in limited supply because HSCs notoriously die or differentiate ex vivo [9]. To this end, several studies exist that employ different methods to expand these cells ex vivo or generate them de novo [10][11][12][13]. This issue hinders their use for a multitude of in vitro applications, such as drug testing platforms and disease modeling systems.…”

mentioning

confidence: 99%

Induction of human hemogenesis in adult fibroblasts by defined factors and hematopoietic coculture

et al. 2019

View full text Add to dashboard Cite

Transcription factor (TF)‐based reprogramming of somatic tissues holds great promise for regenerative medicine. Previously, we demonstrated that the TFs GATA2, GFI1B, and FOS convert mouse and human fibroblasts to hemogenic endothelial‐like precursors that generate hematopoietic stem progenitor (HSPC)‐like cells over time. This conversion is lacking in robustness both in yield and biological function. Herein, we show that inclusion of GFI1 to the reprogramming cocktail significantly expands the HSPC‐like population. AFT024 coculture imparts functional potential to these cells and allows quantification of stem cell frequency. Altogether, we demonstrate an improved human hemogenic induction protocol that could provide a valuable human in vitro model of hematopoiesis for disease modeling and a platform for cell‐based therapeutics. Database Gene expression data are available in the Gene Expression Omnibus (GEO) database under the accession number http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE130361.

show abstract

Long-term ex vivo haematopoietic-stem-cell expansion allows nonconditioned transplantation

Cited by 308 publications

References 29 publications

Haematopoietic stem cell reprogramming and the hope for a universal blood product

Haematopoietic stem cell reprogramming and the hope for a universal blood product

Unleashing the cure: Overcoming persistent obstacles in the translation and expanded use of hematopoietic stem cell-based therapies

Induction of human hemogenesis in adult fibroblasts by defined factors and hematopoietic coculture

Contact Info

Product

Resources

About