Anne-Isabelle S. Reme

Engineered mesenchymal stem cells (MSCs) have emerged as promising therapeutic platforms for healthspan-relevant applications. As agents of tissue repair and modulators of biological aging, MSCs have been widely studied for their capacity to enhance regeneration, restore immune homeostasis, and reduce chronic inflammation associated with age-related decline. This review examines emerging bioengineering strategies designed to overcome key age-related limitations in MSC homing, survival, and paracrine signaling, which have historically constrained their in vivo efficacy. We discuss major engineering approaches, including genetic modification, surface engineering, metabolic reprogramming, and preconditioning, with particular attention to their contributions to longevity-focused applications. Preclinical studies have demonstrated that engineered MSCs and their extracellular vesicles (EVs) yield measurable improvements in therapeutic performance. Reported benefits include prolonged persistence in inflamed tissues, partial reversal of senescence-associated phenotypes, and modulation of pro-aging inflammatory pathways. While MSC-derived EVs may offer potential safety advantages and could reduce certain risks associated with live-cell administration, this remains to be confirmed in well-controlled clinical studies, and significant challenges persist in terms of manufacturing scalability, cargo consistency, and process standardization. The current literature, which is predominantly preclinical, supports the potential of engineered MSC platforms to improve healthspan-relevant outcomes; direct evidence of healthspan extension in humans is not yet available. However, successful clinical translation will require a standardized manufacturing process to ensure therapeutic safety, reproducibility, and efficacy in age-related conditions.

Engineered mesenchymal stem cells (MSCs) have emerged as a promising therapeutic platform for extending healthspan. As agents of tissue repair and modulators of biological aging, MSCs have been widely studied for their capacity to enhance regeneration, restore immune homeostasis, and reduce chronic inflammation associated with age-related decline. This review examines emerging bioengineering strategies designed to overcome key age-related limitations in MSC homing, survival, and paracrine signaling, which have historically constrained their in vivo efficacy. We discuss major engineering approaches, including genetic modification, surface engineering, metabolic reprogramming, and preconditioning, with particular attention to their contributions to longevity-focused applications. Preclinical studies have demonstrated that engineered MSCs and their extracellular vesicles (EVs) yield measurable improvements in therapeutic performance. Reported benefits include prolonged persistence in inflamed tissues, partial reversal of senescence-associated phenotypes, and modulation of pro-aging inflammatory pathways. While MSC-derived EVs appear to offer a safer alternative with lower immunological risk, significant challenges persist in terms of manufacturing scalability, cargo consistency, and process standardization. The literature collectively supports that engineered MSC platforms have significant potential to contribute to healthspan extension. However, successful clinical translation will require a standardized manufacturing process to ensure therapeutic safety, reproducibility and efficacy in age-related conditions.

Hypoxia, characterized by insufficient oxygen saturation, triggers a wide array of vascular responses aimed at enhancing cell survival and proliferation. This process is primarily driven by the activation of oxygen-sensing hypoxia-inducible factors (HIFs). HIF-1α, a key mediator in this context, plays a crucial role in vascular restructuring in response to low oxygen tension and oxygen-independent signaling pathways, making it a promising therapeutic target for ischemic cardiovascular diseases such as peripheral artery disease and coronary artery disease. In this review, we explore both oxygen-dependent and oxygen-independent mechanisms of HIF-1α regulation, the role of the HIF protein family in vessel collateralization, and translational efforts to leverage HIF-1α‘s pivotal role in hypoxia signaling for the development of clinical treatments for ischemic cardiovascular disease.

Hypoxia, or lack of adequate oxygen saturation, activates a vast repertoire of vascular responses to increase cell survival and proliferation, driven primarily by activation of oxygen-sensing hypoxia-inducible factors (HIFs). Key hypoxia mediator HIF-1 alpha is capable of driving vascular restructuring in response to low oxygen tension and oxygen-independent signaling pathways, and thus serves as a promising therapeutic modulator for ischemic cardiovascular diseases such as peripheral artery disease and coronary artery disease. In this review, we discuss oxygen-dependent and oxygen-independent mechanisms of HIF-1 alpha regulation, the HIF protein family’s role in vessel collateralization, and translational efforts seeking to exploit HIF-1 alpha’s key role in hypoxia signaling for the purpose of therapeutic development of clinical treatments for ischemic cardiovascular disease.