Towards Replacement of the Aged Hematopoietic Stem Cell Population

Ultimately, the treatment of aging as a medical condition must include ways to either repair or replace damaged stem cell populations. This is a monumental task, given the sizable number of distinct types of stem cell in the body, but there is progress towards replacement via cell therapy in the case of a few of the better studied and characterized stem cell populations. Arguably the most advanced of this work is focused on replacement of hematopoietic stem cells, the stem cell population responsible for generating blood and immune cells. This is fortunate, as the decline of these stem cells has a profound detrimental effect on the immune system, and the age-related decline of immune function is an important contribution to the frailty of older individuals. Improving hematopoietic function in older individuals is one of the necessary steps that must be taken to reverse immunosenescence.

Transplantation of hematopoietic stem cells, in the form of bone marrow transplantation, has been an ongoing concern for decades, and there has consequently been a great deal of research into the biochemistry of these stem cells, as well as how to move towards therapies that deliver just hematopoietic stem cells rather than tissue. It is now possible to produce patient matched stem cells using reprogramming techniques, potentially eliminating many of the serious issues of rejection and autoimmunity that make hematopoietic stem cell transplant as presently practiced a procedure with significant risk. The major blocking challenge at the moment is how to ensure that enough of the transplanted cells engraft in the bone marrow niches and survive to produce a steady supply of blood and immune cells. This issue has yet to be robustly solved, despite a few promising demonstrations in animal models.

Hematopoietic Differentiation of Human Pluripotent Stem Cells: HOX and GATA Transcription Factors as Master Regulators

Hematopoiesis is a complex process through which hematopoietic stem cells (HSCs) generate all the cell types found in the blood. This originates during the early stages of embryonic development and continues in the bone marrow (BM) throughout adulthood to preserve homeostasis in the blood system. The interest in the expansion and production of HSCs has increased in recent years. After the derivation of human embryonic stem cells (ESCs) and the discovery of cellular reprogramming, much effort has been devoted to obtain HSCs and mature blood cells from human pluripotent stem cells (PSCs).

In addition to their unlimited, yet-to-be realized, therapeutic potential, human PSCs make a very useful tool that can be utilized to understand the signaling pathways involved in hematopoiesis. Recently, long term engraftment and multi-lineage differentiation of hPSCs-derived hematopoietic progenitor cells was achieved after screening large numbers of potential transcription factors that were activated in vivo following transplantation in mice. Ideally, the generation of functional HSCs with the same capacity in vitro would allow deep interrogation of the differentiation process, and, eventually, the generation of therapeutic grade cells.

Human PSCs represent a promising versatile source of cells for regenerative medicine. The fact that they could be derived from patients' somatic cells and undergo clonal expansion in culture makes them ideal for the regeneration of the blood system. Their potential with regard to treating genetic blood disorders could be augmented when combined with genome editing techniques.

However, two main hurdles limit the translation of induced pluripotent stem cell (iPSC) derived HSCs into cellular therapies. First, the generation of functional iPSC-derived HSCs capable of long-term engraftment and full reconstitution of the blood system. Second, the long-term safety of the generated cells. HSCs derived from iPSCs remain transcriptionally and epigenetically distinct from cord blood HSCs. The impact of these differences on the safety and functionality of the generated HSCs is yet to be investigated.

Comments

Blood stem cell replacement and fibrosis of the lyphm nodes are the big hurdles (hand waving away taking thymic rejuvenation and T and B cell ablation through clinical trials).

But you could potentially solve so many auto-immune dieseases and probelms in addition to a failing immune system with aging that this is a tantilizing prize. I wish we were there already. I hope this area is well funded.

I wonder if these hurdles will be surmounted in the next five years, or if it will take 25 years?

Posted by: jimofoz at January 9th, 2020 6:55 AM

Magenta Therapeutics are one well funded company that is taking aim at improving allogenic (donor) or autlogous (self) hematopoietic stem cell transplantation:

https://www.magentatx.com/revolutionizing-medicine/programs/

Magenta have MGTA-145 in clinical trials for better mobilising blood stem cells for collection.

They have three antibody drug conjurgates targeting proteins (CD45-ADC, CD117-ADC, and C300) on the surface of hematopoietic stem cells. Although antibody drug conjurgates have had a difficult time avoiding toxicity in the past as the antibodies persist for so long in the body. Maybe a new technology such as bicyclic peptides could fare better?

https://lifescivc.com/2017/02/poisons-pills-peptides/

Posted by: jimofoz at January 9th, 2020 8:20 AM

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